Novel tricyclic compounds having a TXA2 antagonizing activity represented by formula (I): ##STR1## possess a potent antagonizing against thromboxane A2 and also an antiallergic and/or antihistaminic activity, and are expected to have preventive and therapeutic effects on ischemic diseases, cerebro-vascular diseases, etc.
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8. 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5 H-dibenzo [a,d]-cyclohepten-3-carboxylic acid.
9. 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10, 11-dihydro-5 H-dibenzo[a,d]cyclohepten-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
1. A tricyclic compound represented by formula (I): ##STR262## wherein
represents single bond or double bond; X1 -X2 represents --CH2 --CH2 --, or --CH═CH--; W represents --S-- or ═CH--; n is 1, 2, 3, or 4; one of rA and rB represents hydrogen and the other represents --Y--M wherein Y represents single bond, --CR1 r2 --(CH2)m --, or --CR1 ═CR2 --(CH2)m -- wherein each of r1 and r2 independently represents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus; and M represents --CONR3a r3b wherein each of r3a and r3b independently has the same significances for r3 as described above, or tetrazolyl; each of GA and GB independently represents lower alkyl, halogen, hydroxyl, or lower alkoxyl; each of gA and gB independently represents 0, 1, 2 or 3; Z represents ##STR263## wherein Q represents aryl, aralkyl or aralkenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxyl and methylene dioxy formed together with the ortho-position of the aromatic ring; wherein L represents hydrogen, hydroxyl, or lower alkoxy; and E2 represents single bond, --CO--, or ##STR264## wherein r4 represents hydrogen or lower alkyl; >C═CH--Q wherein Q has the same significance as described above; p is 1, 2 or 3; and a pharmaceutically acceptable salt thereof. 2. A compound according to
3. A compound according to
5. A compound according to 4, wherein Q represents optionally substituted aryl having 6 to 10 carbon atoms, optionally substituted aralkyl having 7 to 20 carbon atoms or optionally substituted aralkenyl having 8 to 18 carbon atoms.
6. A compound according to any one of
7. A compound according to
10. A pharmaceutical composition comprising a pharmaceutical carrier and, as an active ingredient, an effective amount of a tricyclic compound as defined by
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This application is a division of application Ser. No. 616,095, filed Nov. 20, 1990, now U.S. Pat. No. 5,143,922 which is a division of application Ser. No. 281,545, filed Dec. 8, 1988, now U.S. Pat. No. 4,994,463.
The present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A2 (hereafter referred to as TXA2) and possess an antiallergic and/or antihistaminic activity.
It is hitherto known that TXA2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. Further TXA2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA2 is considered to take part in pathological conditions over a wide range. As examples, the following diseases can be exemplified.
(1) Ischemic disease
For example, myocardial infarction, angina pectoris, and thrombosis
(2) Cerebro-vascular disease
For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction
(3) Peripheral vascular diseases and disease caused by unbalanced lipid metabolism
For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism
(4) Inflammatory and allergic disease
For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
(5) Shock
(6) Cancer metastasis
Accordingly, compounds that antagonize the action of TXA2 are expected to have therapeutic effects in preventing or treating one or more of the diseases described above or other diseases involving TXA2. Furthermore, in those instances where use of a particular drug was limited due to side effects mediated by TXA2 or considered to be mediated by TXA2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA2.
In recent years, TXA2 is also thought to play a role in the pathogenesis of allergic diseases, especially of an asthma (cf. J. Allergy Clin. Immunol., 77, 122 (1986); Arch. Pharmacol., 327, 148 (1984)].
As an antagonist of TXA2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986).
Furthermore, an indole compound having the following structure: ##STR2## and the like are disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## and the like are disclosed in Japanese Publisher Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds have a phenylsulfonamide group as a side chain and exhibit an activity of antagonizing TXA2.
On the other hand, in tricyclic compounds represented by the following formula: ##STR4## wherein R0 as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W0 is hydrogen or a substituent such as oxo (═O), methylene (═CH2), hydroxyl, alkoxyl, etc., oxepine derivatives wherein X1 -X2 is --CH2 O--are known as showing antiinflammatory or antiallergic activities, etc. [J. Med. Chem., 19, 941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No. 4,282,365 (Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788; Japanese Published Unexamined Patent Application Nos. 152673/1986; 152674/1986 and 152675/1986].
Further, it is also known that oxepine derivatives wherein R0 is hydrogen or a substituent other than the carboxylic acid group, such as, alkyl, alkoxyl, halogen, etc. and W0 has a (di)alkylaminoalkyl chain via --S-- show antiasthmatic activities [Japanese Published Unexamined Patent Application No. 126883/1983 (EP 0085870A)]. It is also known that derivatives such as oxepine or thiepine (wherein X1 -X2 is --CH2 S--) wherein W0 is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977); Arz.-Forsch., 13, 1039 (1963); ibid., 14, 100 (1964)]. Furthermore, it is also known that derivatives such as cycloheptene (wherein X1 -X2 is --CH═CH--) or thiepine wherein W0 has an alkyl chain substituted with an alicyclic nitrogen-containing heterocyclic group such as piperazine, etc. at the terminal thereof via --NHCO-- are known to have a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (EP 191867A) and 153280/1987].
Further oxepine derivatives having an antiallergic activity wherein R0 has a carboxylic acid group and W0 has a (di)alkylaminoalkyl chain via --S-- are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986, 152670/1986, 152671/1986 and 15672/1986 (all of them correspond to EP 188802A); 152676/1986 and 257981/1986]. Furthermore, oxepine or cycloheptene (wherein X1 -X2 is --CH2 CH2 --) derivatives showing an antihistaminic activity wherein W0 is a (di)alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1986 (EP 214779A)]. Still further, oxepine derivatives wherein W0 is an alkylidene substituted with an alicyclic nitrogen-containing heterocyclic group such as 4-methylpiperazinyl, 4-methylhomopiperazinyl, piperidino, pyrrolidinyl, thiomorpholino or morpholino or with a (di)alkyl-substituted amino at the terminal thereof are known as showing an antiallergic and antiinflammatory activity [Japanese Published Unexamined Patent Application No. 10784/1988 (EP 0235796A)].
Novel and useful TXA2 antagonists are expected to have preventive and therapeutic effects on various diseases, and are in demand. Further antiallergic agents having a TXA2 -antagonizing activity are expected to have preventive and therapeutic effects on allergic diseases, and are in demand.
An object of the present invention is to provide novel tricyclic compounds having a TXA2 - antagonizing activity and antiallergic activity by containing both a carboxylic acid group as the foresaid R0, and, as the aforesaid W0, an alkylthio chain or alkylidene chain substituted at the terminal thereof with an alicyclic nitrogen-containing heterocyclic group having a substituent such as aryl, aralkyl, etc. thereon.
The present invention relates to a tricyclic compound [hereafter referred to as Compound (I); compounds having other formula numbers are also the same] represented by formula (I): ##STR5## wherein represents single bond or double bond; X1 X2 represents --CH2 O--, ##STR6## wherein l represents 0, 1 or 2, --CH2 --CH2 --, or --CH═CH--;
W represents --S--or ═CH--;
n is 1, 2, 3, or 4;
one of RA and RB represents hydrogen and the other represents --Y--M wherein Y represents single bond, --CR1 R2 --(CH2)m --, or --CR1 ═CR2 --(CH2)m -- wherein each of R1 and R2 independently represents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus; and M represents --COOR3 wherein R3 represents hydrogen or lower alkyl, --CONR3a R3b wherein each of R3a and R3b independently has the same significances for R3 as described above, or tetrazolyl;
each of GA and GB independently represents lower alkyl, halogen, hydroxyl, or lower alkoxyl;
each of gA and gB independently represents 0, 1, 2 or 3;
Z represents >N--E1 --Q wherein E1 represents single bond, --CO--, --COO-- wherein the left side of the formula is bound to the nitrogen atom, or --SO2 --; and Q represents optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, aromatic heterocyclic group, or ##STR7## wherein L represents hydrogen, hydroxyl, or-lower alkoxy; E2 represents single bond, --CO--, or ##STR8## wherein R4 represents hydrogen or lower alkyl; and Q has the same significance as described above; >C═CH--Q wherein Q has the same significance as described above; or ##STR9## p is 1, 2 or 3; and a pharmaceutically acceptable salt thereof.
In the definition of Z in formula (I), the aryl is exemplified by phenyl and naphthyl having 6 to 10 carbon atoms, etc.; the aralkyl is exemplified by benzyl, phenethyl, benzhydryl and trityl, etc. having 7 to 20 carbon atoms, etc.; and the aralkenyl is exemplified by styryl and cinnamyl having 8 to 18 carbon atoms, etc. The substituent on each group means independently 1 to 3 substituents on the aromatic ring and includes a group selected from lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxyl and methylenedioxy formed together with the ortho-position thereof. Likewise, the aromatic heterocyclic, group shown by Q represents a group selected from furyl, thienyl, pyridyl, pyrimidinyl, quinolyl and isoquinolyl.
Further in the definition of each group in formula (I), the alkyl moiety in the lower alkyl and lower alkoxyl is a straight or branched alkyl having 1 to 6 carbon, atoms, for example, methy, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.; the halogen includes, for example, fluorine, chlorine, bromine and iodine.
The pharmaceutically acceptable salt of Compound (I) includes an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, etc. which are pharmaceutically acceptable.
As the pharmaceutically acceptable acid addition salt of Compound (I), mention may be made of the inorganic acid salt such as hydrochloride, sulfate, phosphate, etc. and the organic acid salt such as acetate, malate, fumarate, tartarate, citrate, etc. As the pharmaceutically acceptable metal salt, the alkali metal salt such as sodium salt, potassium salt, etc.; alkaline earth metal salt such as magnesium salt, calcium salt, etc. and further the aluminum salt and the zinc salt are appropriate. As the ammonium salt, mention may be made of the salt of ammonium, tetramethylammonium, etc. As the pharmaceutically acceptable organic amine addition salt, mention may be made of an addition salt of morpholine, piperidine, etc. As the pharmaceutically acceptable amino acid addition salt, an addition salt of lysine, glycine, phenylalanine and the like are mentioned.
Hereafter processes for producing Compound (I) are described but the production of Compound (I) is not deemed to be limited thereto. Further in various processes, the reaction conditions can be appropriately chosen from those described below.
The reaction solvent may be chosen from water or an organic solvent which does not participate in the reaction and can be used alone or in combination. The organic solvent includes, for example, an alcohol such as methanol, ethanol, propanol, isopropanol, etc.; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, etc.; a hydrocarbon such as benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroin, decalin, etc.; a ketone such as acetone, methyl ethyl ketone, etc., an amide such as formamide, dimethylformamide, hexamethylphosphoric triamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide, sulfolane or a halogenated hydrocarbon such as methylene chloride, dichloroethane, tetrachloroethane, chloroform or carbon tetrachloride, etc. Further in case that bases or acids later described are liquid, they may also be used as a solvent.
As the appropriate base, an inorganic or organic base can be used. These bases include an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example, sodium carbonate, sodium hydrogencarbonate or potassium carbonate; an alkali metal acetate, for example, sodium acetate or potassium acetate; an alkali metal alkoxide, for example, sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an organic metal compound, for example, sodium hydride, n-butyl lithium, sec-butyl lithium; and an organic amine, for example, triethylamine, tri-n-butylamine, pyridine, N,N-dimethylaminopyridine, picoline, lutidine, N,N-dimethylaniline, dicyclohexylmethylamine, N-methylpiperidine, morpholine, diazabicyclooctane, diazabicycloundecene or N7-benzyltrimethylammonium hydroxide (Triton B), etc.
As the appropriate acid, an inorganic or organic acid or Lewis acid can be used. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, hypochloric acid, sulfurous acid or nitrous acid, etc. Examples of the organic acid include formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid or methanesulfonic acid, etc. Examples of the Lewis acid include aluminum chloride, zinc chloride, tin chloride, boron trifluoride, boron ttifluoride diethyl ether complex, titanium tetrachloride, etc.
The reaction temperature is generally from -80°C to a boiling point of a solvent. Heating without a solvent is also possible. The reaction may generally be carried out under normal pressure but it is also possible to apply pressure. In this case, the reaction temperature may be raised to a temperature higher than the boiling point of a solvent.
The reaction time is generally in a range of one minute to one week.
In the following description, preferred reaction conditions are given.
Further in the following description, the tricyclic moiety which does not directly participate in the reaction: ##STR10## wherein , X1 -X2, RA, RB, GA, GB, gA and gB have the same significances as described above; is sometimes referred to as: ##STR11##
Compound (I) can be prepared from Compound (II) or from Compounds (IIIa through d), etc. obtained from Compound (II) according to the following reaction steps: ##STR12## wherein ##STR13## has the same significance as described above; R5 represents lower alkyl, Hal represents halogen and Ph represents phenyl.
Herein the halogen shown by Hal represents chlorine, bromine and iodine and the lower alkyl has the same significance as defined for the lower alkyl in each group in formula (I).
Compounds (II) are either described in J. Med. Chem., 19, 941 (1976); ibid., 21, 1035 (1978); ibid., 20, 1557 (1977); ibid., 20, 1499 (1977); ibid., 29, 2347 (1986); ibid., 21, 633 (1978); ibid., 20, 456 (1977); U.S. Pat. Nos. 4,172,949 and 4,282,365; Japanese Published Unexamined Patent Application Nos. 21679/1983; 28972/1985; 152669/1986; 152672/1986; 152673/1986; 152675/1986 and 10784/1988 etc. or can be synthesized according to methods described in these publications or in a manner similar thereto.
Moreover Compounds (IIIA to d) can be synthesized from Compound (II) according to methods described in Japanese Published Unexamined Patent Application Nos. 150083/1981; 28972/1985; 152670/1986; 152671/1986; 152672/1986; 152675/1986 and 10784/1988, etc. or in a manner similar thereto.
PAC [Synthesis of Compound (Ia) in Compound (I), wherein W is --S--(part 1)] ##STR14## wherein X1 -X2, RA, RB, GA, GB, Z, gA, gB, n and p have the same significances as described above.Compound (Ia) can be obtained from Compounds (IIIA to c) and (IVa) according to the following reaction step. ##STR15## wherein A1 represents OH, OR5 or Hal; and ##STR16## Z, R5, Hal and p have the same significances as described above.
Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIA) with 1 to 5 molar equivalents of an appropriate dehydration condensing agent, for example, trifluoroacetic anhydride at from 0°C to room temperature for 1 to 24 hours in an inert solvent such as methylene chloride, chloroform, etc., then adding 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof (for example, hydrochloride, hydrobromide, acetate, trifluoroacetate, p-toiuenesulfonate, etc.; theisame is applied hereafter) to the reaction solution and carrying out the reaction at 0°C to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.
Likewise, Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIB) with 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc., at 0°C to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.
Furthermore, Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIC) with 1 to 10 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, dimethylformamide, etc., at 0°C to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of a base such as triethylamine, sodium hydride, etc.
PAC [Synthesis of Compound (Ia) (part 2)]Likewise, Compound (Ia) can be obtained from Compounds (IIIa-c) according to the following reaction steps.
Firstly, Compound (VIb) or (VIc) is prepared from Compounds (IIIa-c) according to the following reaction steps: ##STR17## wherein ##STR18## , A1, Hal and n have the same significances as described above; and R6 represents a group capable of being split as OR6.
Herein, R6 means, for example, alkylsulfonyl such as methanesulfonyl, trifluoromethanesulfonyl, etc. and arylsulfonyl such as phenylsulfonyl, p-toluenesulfonyl, etc.
The corresponding Compound (VIa) or (VIc) can be obtained by reacting Compound (IIIA) with 1 to 5 molar equivalents of an appropriate dehydrating and condensing agent, for example, trifluoroacetic anhydride, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of from 0°C to room temperature for 1 to 24 hours, then adding 1 to 10 molar equivalents of an alcohol (Va) or its halide (Vb) to this reaction solution and carrying out the reaction at a temperature of between room temperature and the boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours.
Compound (VIa) or (VIc) can also be obtained by reacting Compound (IIIB) or (IIIC) with 1 to 10 molar equivalents of an alcohol (Va) or its halide (Vb) in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of between room temperature and the boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, or an appropriate base such as triethylamine for 1 to 24 hours.
Further, the thus obtained Compound (VIa) may be reacted with 1 to 5 molar equivalents of Hal-R6 or (R6)2 O (wherein R6 and Hal have the same significances as described above) in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from -50°C to room temperature for 1 to 24 hours to give Compound (VIb).
Furthermore, compound (VIa) may be reacted (1) with 1 to 5 molar equivalents of a halogenating agent, for example, thionyl chloride, in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from 0°C to room temperature for 1 to 24 hours; (2) with 1 to 10 molar equivalents of an alkyl halide such as methyl iodide in an inert solvent such as benzene in the presence of 1 to 10 molar equivalents of triphenylphosphine and 1 to 10 molar equivalents of diethyl azodicarboxylate at a temperature of from -20°C to a boiling point of the solvent for 1 to 24 hours; or (3) with 1 to 10 molar equivalents of a halogenating agent, for example, methanesulfonyl chloride, in dimethylformamide in the presence of 1 to 10 molar equivalents of a base such as lithium chloride, etc., at a temperature of from -20° to 100°C for 1 to 24 hours, whereby Compound (VIc) is obtained.
Where Compound (VIc) is the chloride (Hal is Cl) or bromide (Hal is Br), the compound may be reacted further with an iodide, for example, sodium iodide, in a polar solvent such as acetonitrile to give the iodide (Hal is I). Compound (VIb) can be converted into Compound (VIc) under similar conditions.
Compound (VIb) or (VIc) can be converted into Compound (Ia) according to the following reaction step: ##STR19## wherein A2 represents OR6 or Hal; and R6, Hal, ##STR20## Z, p and n have the same significances as described above.
Compound (Ia) can be obtained by reacting Compound (VIb) or Compound (VIc) with 1 to 10 molar equivalents of Compound (VII), if necessary, in the presence of a molar equivalent to a largely excessive amount of a base such as sodium carbonate, triethylamine, pyridine, Triton B, sodium hydride, etc., at a temperature of between room temperature and the boiling point of the solvent for 1 to 48 hours in an inert solvent such as methylene chloride, chloroform, dichloroethane, dimethylformamide, dioxane, etc.
Further the reaction of Compound (VIc) with Compound (VII) may also be carried out in the presence of an iodide, for example, sodium iodide or potassium iodide.
PAC [Synthesis of Compound (Ib) in Compound (I), wherein W is ═CH-- (Part 1)) ##STR21## wherein X1 -X2, RA, RB, GA, GB, z, n, gA, gB and p have the same significances as described above.Compound (Ib) can be prepared according to the following reaction steps: ##STR22## wherein ##STR23## Z, Ph, n and p have the same significances as described above.
Firstly, a phosphonium salt (VIIIb): ##STR24## wherein Z, Hal, Ph, n and p have the same significances as described above, obtained by reacting triphenylphosphine (Ph3 P) with a halide: ##STR25## is treated with a molar equivalent of a base such as n-butyl lithium, etc. in an inert solvent, for example, tetrahydrofuran, etc., at 0°C to room temperature to give an slide (VIIIa).
Compound (Ib) can be obtained by reacting 1 to 5 molar equivalents, based on Compound (II), of Compound (VIIIa), after or without isolation, with Compound (II) in an inert solvent, for example, tetrahydrofuran, etc., at a temperature of from 0°C and a boiling point of the solvent.
PAC [Synthesis of Compound (Ib) (part 2)]Compound (Ib) can also be obtained from Compound (II) according to the following reaction steps: ##STR26## wherein ##STR27## Z, Hal, n and p have the same significances as described above.
Firstly, Compound (II) is reacted with 1 to 5 molar equivalents of Grignard reagent (IVc) in an inert solvent such as tetrahydrofuran, diethyl ether, etc., at a temperature of from 0°C to room temperature, for 1 to 48 hours to give an alcohol (IX).
Compound (IVc) can be obtained by reacting corresponding Compound (IVb) with 0.5 to 2 molar equivalents of magnesium in an inert solvent such as tetrahydrofuran, diethyl ether, etc., if necessary and desired, in the presence of a trace amount of iodine, at a temperature of from 0° C. to a boiling point of the solvent for 0.5 to 12 hours. The Grignard reagent thus formed is generally used in the following reaction without isolating the same.
The thus obtained Compound (IX) can be subjected to dehydration to give Compound (Ib). For the dehydration, a method which comprises performing the reaction in an inert solvent such as dioxane, etc., in the presence of an acid, for example, p-toluenesulfonic acid, etc., at a temperature of from room temperature to boiling point of the solvent for 1 to 12 hours, or a method which comprises reacting with a halogenating agent such as thionyl chloride, etc., in an organic base such as pyridine, etc. at a temperature of from 0°C to a boiling point of the solvent for 1 to 12 hours, or the like is adopted.
PAC [Synthesis of Compound (Ib) (part 3)]Firstly, the carbonyl group of Compound (II) is converted into Compound (Xb) according to the following reaction steps: ##STR28## wherein ##STR29## Ph and n have the same significances as described above, and R7 represents a hydroxyl-protecting group.
Herein, as the hydroxyl-protecting group, groups generally use as protective groups for an alcoholic hydroxyl may be used. A preferred protecting group is, for example, tetrahydropyranyl or the like.
Firstly, an ylide (VIIIc) in which hydroxyl is protected by an appropriate protective group (for example, tetrahydropyranyl, etc.) is formed in an inert solvent, for example, tetrahydrofuran (J. Org. Chem., 44, 3760 (1979)].
Then, the formed ylide (VIIIC) is reacted with 0.2 to 1 molar equivalent of Compound (II) at a temperature of from -78°C to the boiling point of the solvent for 1 to 48 hours to give Compound (Xa).
Compound (Xa) can be converted into Compound (Xb) by removing the protective group. The removal of protective group can be conducted in a conventional manner; in the case of using, for example, tetrahydropyranyl as a protective group, Compound (Xa) is treated with an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc. in a suitable hydrated solvent such as hydrated dioxane, hydrated tetrahydrofuran, etc., at a temperature of from 0°C to a boiling point of the solvent for 1 to 24 hours to give Compound (Xb).
Compound (Xb) can be led to Compound (Ib) via Compound (Xc) or Compound (Xd) by the following reaction steps: ##STR30## wherein ##STR31## Z, R6, Hal, n and p have the same significances as described above.
The reactions can be preferred in a manner similar to the method for leading from Compound (VIa) to Compound (Ia) described in Method 1-2.
PAC [Synthesis of Compound (Ib-1) in Compound (Ib) wherein n is 1] ##STR32## wherein X1 -X2, RA, RB, GA, GB, z, gA, gB and p have the same significances as described above.Compound (Ib-1) can be prepared according to the following reaction steps: ##STR33## wherein ##STR34## Z, R6, Hal and p have the same significances as described above; [CH2 O] represents formaldehyde and/or a polymer thereof; R8a and R8b, which may be the same or different, each represents lower alkyl or may be combined to nitrogen adjacent thereto to form a heterocyclic ring and R9 represents lower alkyl.
Herein, the lower alkyl in the definitions of R8a, R8b and R9 has the same significance as described for the lower alkyl in formula (I). As the heterocyclic ring formed by R8a and R8b, mention may be made of pyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine, N-methylhomo-piperazine and the like.
Compound (IIID) is reacted with 1 to 10 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, either in a hydrohalogenic acid, preferably hydrochloric acid or in an inert solvent, for example, dioxane, saturated with hydrogen chloride and, if necessary and desired, in the presence of a strong acid such as sulfuric acid or trifluoroacetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 24 hours to give Compound (Xd-1).
Further Compound (Xb-1) can be obtained under almost the same conditions as described above except that no hydrohalogenic acid is added.
Furthermore, Compound (Xd-1) can also be obtained as follows. That is, Compound (IIID) is reacted with 1 to 2 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, and 1 to 3 molar equivalents of a secondary amine (XI) and trifluoroacetic acid, in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary and desired, in the presence of acetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 48 hours to give Compound (Xe) or acid addition salts thereof. Compound (Xe) can be led to Compound (Xd-1) by reacting with 1 to 10 molar equivalents of a halocarbonate, preferably ethyl chloroformate in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary, in the presence of a base such as triethyl amine and sodium acetate between at 0°C and the boiling point of the solvent for 1 to 48 hours.
The thus obtained Compounds (Xb-1) and (Xd-1) can be converted into Compound (Ib-1) as in the synthesis of Compound (Ib) from the corresponding Compounds (Xb) and (Xd) described in Method 2-3.
Further Compound (Ib-1) can also be obtained according to the method for obtaining Compound (Xe) from Compound (IIId) in which Compound (VII) is used in place of Compound (XI).
PAC [Synthesis of Compound (Ic) in Compound (I), wherein Z is >N--E1 --Q] ##STR35## wherein , X1 -X2, RA, RB, GA, GB, W, E1, Q, gA, gB, n and p have the same significances as described above.Compound (Ic) can be prepared from Compounds (XII) and (XIII) obtained in a manner similar to Methods 1 and 2 described above by the following reaction steps: ##STR36## wherein ##STR37## W, E1, Q, n and p have the same significances as described above and A3 represents a leaving group in --E1 --Q.
Herein, in the case that E1 is single bond, leaving group A3 represents halogen such as chlorine, bromine, iodine, etc. and in the case that E1 is --CO--, A3 --E1 --Q represents HOOC--Q (A3 is OH) or a carboxylic acid reactive derivative. The carboxylic acid reactive derivative includes an acid halide (acid chloride, acid bromide, etc.), an acid anhydride (acid anhydride formed with a dehydrating condensing agent such as N,N'-dicyclohexylcarbodiimide, etc., in the reaction system, commercially available acid anhydrides, etc.), an activated ester (p-nitroplienyl ester, N-hvdroxysuccinimide ester, etc.), a mixed acid anhydride (monoethyl carbonate, monoisobutyl carbonate, etc.) and the like. Further in the case that E1 is --COO--, A3 represents halogen as described above and in the case that E1 is --SO2 --, A3 represents halogen or --O--SO2 --Q.
Compound (Ic) can be obtained by reacting Compound (XII) or acid addition salts thereof with 1 to 5 molar equivalents of Compound (XIII), either in an inert solvent such as methylene chloride, chloroform, etc., in the presence of a base such as pyridine, etc., or in a basic organic solvent such as pyridine or triethylamine, etc., at a temperature of 0°C to room temperature for 1 to 24 hours.
PAC Synthesis of Compound (Id) in Compound (I), wherein M is --COOH] ##STR38## wherein one of RA1 and RB1 represents --Y--COOH and the other represents hydrogen; and , X1 -X2, GA, GB, W, Z, Y, n, gA, gB and p have the same significances as described above.Compound (Id) can be obtained by hydrolysis of the corresponding carboxylic acid ester.
That is, Compound (Id) can be obtained by subjecting Compound (Ie) [in Compound (I), compound wherein M is --COOR3c (wherein R3c represents lower alkyl in the definitions for R3 described above)] synthesized according to Methods 1 to 3, to an appropriate hydrolysis method, for example, by reacting with a molar equivalent to an excess of sodium hydroxide or potassium hydroxide, etc. in a solvent mixture of a lower alcohol such as methanol, ethanol, etc. and water, at a temperature of from room temperature to the boiling point of the solvent for 1 to 48 hours.
PAC [Synthesis of Compound (Id-1) in Compound (I), wherein Y is single bond] ##STR39## wherein one of RA2 and RB2 represents --COOH and the other represents hydrogen; and , X1 -X2, GA, GB, W, Z, n, gA, gB and p have the same significances as described above.Compound (Id-1) can be obtained according to the following reaction steps: ##STR40## wherein one of HalA and HalB represents Hal and the other represents hydrogen; and , X1 -X2, RA2, RB2, GA, GB, W, Z, Hal, n, gA, gB and p have the same significances as described above.
Compound (Id-1) can be obtained by carboxylating Compound (XIV) synthesized from Compound (II-1) in a manner similar to Methods 1 to 3.
Carboxylation can be performed by reacting, for example, Compound (XIV) with 1 molar equivalent of a metallizing agent, e.g., n-butyl lithium, in an inert solvent such as tetrahydrofuran, etc., at a temperature of from -78°C to room temperature, for 10 minutes to 12 hours followed by reacting the resulting reaction mixture with 1 molar equivalent to a largely excessive amount of carbon dioxide at a temperature of from -78°C to room temperature, for 10 minutes to 12 hours. Alternatively, Compound (Id-1) can be obtained by preparing the corresponding Grignard reagent from Compound (XIV) and magnesium in an inert solvent such as diethyl ether, etc. in a manner similar to Method 2-2 and reacting the reagent with carbon dioxide, and the like method.
In the methods for production shown by Methods 1 through 4, where groups defined in Compound (I) change under reaction conditions for practicing the method or are inappropriate for practicing the method, the groups may be subjected to conventional means used in organic synthesis chemistry, for example, means for protecting functional groups, means for removing protection, etc. [for example, cf., Green, Protective Groups in Organic Synthesis, John Wiley & Sons Incorporated (1981)], methods for oxidation, reduction, hydrolysis, etc. [for example, cf., SHIN-JIKKEN KAGAKU KOZA, vols. 14 and 15, Maruzen (1977)].
For example, in case that group M is --COOH, 4,4-dimethyloxazoline, etc. are preferably used as a protecting group for --COOH (for example, Japanese Published Unexamined Patent Application No. 10784/1988) in the method in which the corresponding ester is hydrolyzed (cf. Method 4-1 described above) or in the reaction using a Grignard reagent (cf., for example, Method 2-2). Further, a desired compound can be obtained by hydrolyzing (removing a protecting group in) a compound obtained by Methods 1 through 4, etc. in which group --Y--M is --Y'--CH2 OR10 [wherein Y' represents a group obtained by removing CH2 from Y and R10 represents a protecting group for hydroxyl (e.g., acetyl, tetrahydropyranyl, etc.)] to convert into --Y'--CH2 OH and oxidizing the compound.
The intermediates and objective compounds in the respective methods described above can be isolated and purified by purification methods conventionally used in organic synthesis chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various column chromatographies, etc. Further the intermediates may also be provided in the subsequent reaction, without being particularly purified.
In Compound (I) obtained by the foregoing methods, compounds wherein W is shown by ═CH-- include geometrical isomers of E-form and Z-form with respect to stereochemistry. In general, the methods described above give a mixture of these isomers. Isolation and purification of these isomers can be made in a conventional manner in organic synthesis chemistry, for example, column chromatography, recrystallization, etc. It is also possible to isolate the isomers at stages of intermediates (Xa to Xe) by the various methods described above.
Further, if desired, E- and Z-forms may be isomerized from each other. This can be made by treating each isomer under reflux in, e.g., acetic acid, for 1 to 24 hours, in the presence of an appropriate acid catalyst such as p-toluenesulfonic acid, etc.
In the present invention, Compound (I) includes not only the E/Z isomers described above but also all possible stereoisomers and a mixture thereof.
When the synthesis yields Compound (I) in the form of a salt and such salt is a desired product, the thus formed compound (I) may be purified as is.
When Compound (I) is obtained in a free form, salts may be formed in a conventional manner. Furthermore, Compound (I) and pharmaceutically acceptable salts thereof may also be present in the form of addition products to water or various solvents; these adducts including the pharmaceutically acceptable salts are also included in the present invention.
Specific examples of Compound (I) obtained by various methods are shown in Table 1.
Numbering of substitution positions in Table 1 and Table 6 later described does not necessarily harmonize with the correct nomenclature [cf. see (NOTE) below]; but for purpose of simplicity, numbering of the substitution positions is systematically made as illustrated below. ##STR41##
(NOTE)
In cycloheptene derivatives (wherein X1 -X2 is --CH2 CH2 -- or --CH═CH--), despite the positional number in the general formula above, for example, a substituent on the carbon at the 2-position in the formula above is correctly given as a substituent at the 3-position. However, in the tables, according to the positional numbering in the formula described above, --COOH on the carbon at the 2-position is indicated to be 2-COOH (correctly 3-COOH).
| TABLE 1 |
| __________________________________________________________________________ |
| ##STR42## |
| X1 X2 |
| ##STR43## RA /RB |
| No.Compound |
| __________________________________________________________________________ |
| CH2 O |
| ##STR44## |
| ##STR45## 2-COOCH3 2-COOH |
| 1a 1b |
| ##STR46## |
| ##STR47## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 2a 2b |
| " |
| ##STR48## |
| ##STR49## 2-CH2 CH2 |
| COOCH3 2-CH2 |
| CH2 COOH |
| 3a 3b |
| " |
| ##STR50## |
| ##STR51## 2-CH(CH3)COOCH3 |
| 2-CH(CH3)COOH |
| 4a 4b |
| " |
| ##STR52## |
| ##STR53## |
| ##STR54## 5 |
| " |
| ##STR55## |
| ##STR56## 3-COOCH3 3-COOH |
| 6a 6b |
| " |
| ##STR57## |
| ##STR58## 9-COOCH3 9-COOH |
| 7a 7b |
| " |
| ##STR59## |
| ##STR60## 2-COOCH3 2-COOH |
| 8a 8b |
| " |
| ##STR61## |
| ##STR62## 2-COOCH3 2-COOH |
| 9a 9b |
| CH2 O |
| ##STR63## |
| ##STR64## 2-COOCH3 2-COOH |
| 10a 10b |
| " |
| ##STR65## |
| ##STR66## 2-COOCH3 2-COOH |
| 11a 11b |
| " |
| ##STR67## |
| ##STR68## 2-COOCH3 2-COOH |
| 12a 12b |
| " |
| ##STR69## |
| ##STR70## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 13a 13b |
| " |
| ##STR71## |
| ##STR72## 2-COOCH3 2-COOH |
| 14a 14b |
| " |
| ##STR73## |
| ##STR74## 2-COOCH3 2-COOH |
| 15a 15b |
| " |
| ##STR75## |
| ##STR76## 2-COOCH3 2-COOH |
| 16a 16b |
| " |
| ##STR77## |
| ##STR78## 2-COOCH3 2-COOH |
| 17a 17b |
| " |
| ##STR79## |
| ##STR80## 2-COOCH3 2-COOH |
| 18a 18b |
| " |
| ##STR81## |
| ##STR82## 2-COOCH3 2-COOH |
| 19a 19b |
| " |
| ##STR83## |
| ##STR84## 2-COOCH3 2-COOH |
| 20a 20b |
| CH2 O |
| ##STR85## |
| ##STR86## 2-COOCH3 2-COOH |
| 21a 21b |
| " |
| ##STR87## |
| ##STR88## 2-COOCH3 2-COOH |
| 22a 22b |
| " |
| ##STR89## |
| ##STR90## 2-COOCH3 2-COOH |
| 23a 23b |
| " |
| ##STR91## |
| ##STR92## 2-COOCH3 2-COOH |
| 24a 24b |
| " |
| ##STR93## |
| ##STR94## 2-COOCH3 2-COOH |
| 25a 25b |
| " |
| ##STR95## |
| ##STR96## 2-COOCH3 2-COOH |
| 26a 26b |
| " |
| ##STR97## |
| ##STR98## 2-COOCH3 2-COOH |
| 27a 27b |
| " |
| ##STR99## |
| ##STR100## 2-COOCH3 2-COOH |
| 28a 28b |
| " |
| ##STR101## |
| ##STR102## 2-COOCH3 2-COOH |
| 29a 29b |
| " |
| ##STR103## |
| ##STR104## 2-COOCH3 2-COOH |
| 30a 30b |
| " |
| ##STR105## |
| ##STR106## 2-COOCH3 2-COOH |
| 31a 31b |
| " |
| ##STR107## |
| ##STR108## 2-COOCH3 2-COOH |
| 32a 32b |
| CH2 O |
| ##STR109## |
| ##STR110## 2-COOCH3 2-COOH |
| 33a 33b |
| " |
| ##STR111## |
| ##STR112## 2-COOCH3 2-COOH |
| 34a 34b |
| " |
| ##STR113## |
| ##STR114## 2-COOCH3 2-COOH |
| 35a 35b |
| " |
| ##STR115## |
| ##STR116## 2-COOCH3 2-COOH |
| 36a 36b |
| " |
| ##STR117## |
| ##STR118## 2-COOCH3 2-COOH |
| 37a 37b |
| " |
| ##STR119## |
| ##STR120## 2-COOCH3 2-COOH |
| 38a 38b |
| " |
| ##STR121## |
| ##STR122## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 39a 39b |
| " |
| ##STR123## |
| ##STR124## 2-CH(CH3)COOCH3 |
| 2-CH(CH |
| 40a 40b3 |
| " |
| ##STR125## |
| ##STR126## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 41a 41b |
| " |
| ##STR127## |
| ##STR128## 2-CH2 CH2 |
| COOCH3 2-CH2 |
| CH2 COOH |
| 42a 42b |
| " |
| ##STR129## |
| ##STR130## 2-COOCH3 2-COOH |
| 43a 43b |
| " |
| ##STR131## |
| ##STR132## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 44a 44b |
| CH2 O |
| ##STR133## |
| ##STR134## 2-COOCH3 2-COOH |
| 45a 45b |
| " |
| ##STR135## |
| ##STR136## 2-COOCH3 2-COOH |
| 46a 46b |
| " |
| ##STR137## |
| ##STR138## 2-COOCH3 2-COOH |
| 47a 47b |
| " |
| ##STR139## |
| ##STR140## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 48a 48b |
| " |
| ##STR141## |
| ##STR142## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 49a 49b |
| " |
| ##STR143## |
| ##STR144## 2-COOCH3 2-COOH |
| 50a 50b |
| " |
| ##STR145## |
| ##STR146## 2-COOCH3 2-COOH |
| 51a 51b |
| " |
| ##STR147## |
| ##STR148## 2-COOCH3 2-COOH |
| 52a 52b |
| " |
| ##STR149## |
| ##STR150## 2-COOCH3 2-COOH |
| 53a 53b |
| " |
| ##STR151## |
| ##STR152## 2-COOCH3 2-COOH |
| 54a 54b |
| " |
| ##STR153## |
| ##STR154## 2-COOCH3 2-COOH |
| 55a 55b |
| " |
| ##STR155## |
| ##STR156## 2-COOCH3 2-COOH |
| 56a 56b |
| CH2 O |
| ##STR157## |
| ##STR158## 2-COOCH3 2-COOH |
| 57a 57b |
| " |
| ##STR159## 2-COOCH3 2-COOH |
| 58a 58b |
| " |
| ##STR160## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 59a 59b |
| " |
| ##STR161## |
| ##STR162## 2-COOCH3 2-COOH |
| 60a 60b |
| " |
| ##STR163## |
| ##STR164## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 61a 61b |
| " |
| ##STR165## |
| ##STR166## 2-COOCH3 2-COOH |
| 62a 62b |
| " |
| ##STR167## |
| ##STR168## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 63a 63b |
| " |
| ##STR169## |
| ##STR170## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 64a 64b |
| " |
| ##STR171## |
| ##STR172## 2-COOCH3 2-COOH |
| 65a 65b |
| " |
| ##STR173## |
| ##STR174## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 66a 66b |
| " |
| ##STR175## |
| ##STR176## 2-COOCH3 2-COOH |
| 67a 67b |
| CH2 O |
| ##STR177## |
| ##STR178## 2-COOCH3 2-COOH |
| 68a 68b |
| " |
| ##STR179## |
| ##STR180## 2-COOCH3 2-COOH |
| 69a 69b |
| " |
| ##STR181## |
| ##STR182## 2-COOCH3 2-COOH |
| 70a 70b |
| " |
| ##STR183## |
| ##STR184## 2-COOCH3 2-COOH |
| 71a 71b |
| " |
| ##STR185## |
| ##STR186## 2-COOCH3 2-COOH |
| 72a 72b |
| " |
| ##STR187## |
| ##STR188## 2-COOCH3 2-COOH |
| 73a 73b |
| " |
| ##STR189## |
| ##STR190## 2-COOCH3 2-COOH |
| 74a 74b |
| " |
| ##STR191## |
| ##STR192## 2-COOCH3 2-COOH |
| 75a 75b |
| " |
| ##STR193## |
| ##STR194## 2-COOCH3 2-COOH |
| 76a 76b |
| " |
| ##STR195## |
| ##STR196## 2-COOCH3 2-COOH |
| 77a 77b |
| " |
| ##STR197## |
| ##STR198## 2-COOCH3 2-COOH |
| 78a 78b |
| " |
| ##STR199## |
| ##STR200## 2-COOCH3 2-COOH |
| 79a 79b |
| CH2 O |
| ##STR201## |
| ##STR202## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 80a 80b |
| " |
| ##STR203## |
| ##STR204## 2-CH(CH3)COOCH3 |
| 2-CH(CH3)COOH |
| 81a 81b |
| " |
| ##STR205## |
| ##STR206## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 82a 82b |
| " |
| ##STR207## |
| ##STR208## 2-CH2 CH2 |
| COOCH3 2-CH2 |
| CH2 COOH |
| 83a 83b |
| " |
| ##STR209## |
| ##STR210## 2-COOCH3 2-COOH |
| 84a 84b |
| " |
| ##STR211## |
| ##STR212## 2-COOCH3 2-COOH |
| 85a 85b |
| " |
| ##STR213## |
| ##STR214## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 86a 86b |
| " |
| ##STR215## |
| ##STR216## 2-CH(CH3)COOCH3 |
| 2-CH(CH3)COOH |
| 87a 87b |
| " |
| ##STR217## |
| ##STR218## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 88a 88b |
| " |
| ##STR219## |
| ##STR220## 2-CH2 CH2 |
| COOCH3 2-CH2 |
| CH2 COOH |
| 89a 89b |
| " |
| ##STR221## |
| ##STR222## 2-COOCH3 2-COOH |
| 90a 90b |
| " |
| ##STR223## |
| ##STR224## 2-C(CH3)2 |
| COOCH3 2-C(CH3).s |
| ub.2 COOH 91a 91b |
| " |
| ##STR225## |
| ##STR226## 2-COOCH3 2-COOH |
| 92a 92b |
| CH2 O |
| ##STR227## |
| ##STR228## 2-COOCH3 2-COOH |
| 93a 93b |
| " |
| ##STR229## |
| ##STR230## 2-COOCH3 2-COOH |
| 94a 94b |
| " |
| ##STR231## |
| ##STR232## 2-COOCH3 2-COOH |
| 95a 95b |
| " |
| ##STR233## |
| ##STR234## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 96a 96b |
| " |
| ##STR235## |
| ##STR236## 2-COOCH3 2-COOH |
| 97a 97b |
| " |
| ##STR237## |
| ##STR238## 2-CH2 COOCH3 |
| 2-CH2 COOH |
| 98a 98b |
| CH2 S |
| ##STR239## 2-COOCH3 2-COOH |
| 99a 99b |
| " |
| ##STR240## 2-COOCH3 2-COOH |
| 100a 100b |
| CH2 CH2 |
| ##STR241## 2-COOCH3 2-COOH |
| 101a 101b |
| " |
| ##STR242## 2-COOCH3 2-COOH |
| 102a 102b |
| CHCH |
| ##STR243## 2-COOCH3 2-COOH |
| 103a 103b |
| " |
| ##STR244## 2-COOCH3 2-COOH |
| 104a 104b |
| __________________________________________________________________________ |
The thus prepared Compound (I) possesses a potent TXA2 antagonizing activity and some of them also exhibit an antiallergic activity and/or antihistaminic activity. Preferred examples of Compound (I) are shown in Table 2.
Names of the compounds given in Table 2, reference examples and examples later described are indicated by correct nomenclature.
| TABLE 2 |
| ______________________________________ |
| Compound No. |
| ______________________________________ |
| 11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11- |
| 1b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11- |
| 2b |
| dihydrodibenz[b,e]oxepin-2-acetic acid |
| 11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11- |
| 11b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[2-(4-Chlorobenzyl-1-piperazinyl)ethyl]thio-6,11- |
| 12b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 2-Methyl-2-[11-[2-(4-chlorobenzyl-1-piperazinyl)- |
| 13b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]- |
| 17b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2- |
| carboxylic acid |
| 11-[2-(4-Benzyl-1-homopiperazinyl)ethyl]thio-6,11- |
| 32b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11- |
| 37b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11- |
| 38b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11- |
| 39b |
| dihydrodibenz[b,e]oxepin-2-acetic acid |
| 2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)- |
| 41b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11-[2-[4-(4-Chlorobenzyl)-1-piperidinyl]ethyl]thio-6,11- |
| 43b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 2-Methyl-2-[11-[2-[4-(4-chlorobenzyl-1-piperidinyl)- |
| 44b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]- |
| 47b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2- |
| carboxylic acid |
| 11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]- |
| 48b |
| ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2- |
| acetic acid |
| 2-Methyl-2-[11-[2-[4-[2(3H)-benzimidazolon-1-yl]- |
| 49b |
| piperidino]ethyl]thio-6,11-dihydrodibenz[b,e]- |
| oxepin-2-carboxylic acid |
| 11-[2-[1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on- |
| 58b |
| 8-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin- |
| 2-carboxylic acid |
| 2-Methyl-2-[11-[2-[1-phenyl-1,3,8-triazaspiro[4.5]- |
| 59b |
| decan-4-one-8-yl]ethyl]thio-6,11-dihydrodibenz- |
| [b,e]oxepin-2-yl]propionic acid |
| 11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11- |
| 62b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11- |
| 63b |
| dihydrodibenz[b,e]oxepin-2-acetic acid |
| 2-Methyl-2-[11-[3-(4-benzyl-1-piperazinyl)propylidene- |
| 64b |
| 6,11-dihydrodibenz[b,e]oxepin-2-yl]propionic acid |
| 11-[3-[4-(4-Chlorobenzyl-1-piperazinyl)propylidene]- |
| 65b |
| 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperazinyl)- |
| 66b |
| propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11-[2-[4-(4-Thienylsulfonyl)-1-piperazinyl]- |
| 79b |
| ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic |
| acid |
| 11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]- |
| 80b |
| ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic |
| acid |
| 2-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]- |
| 81b |
| ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 2-Methyl-2-[11-[2-[4-(2-thienylsulfonyl-1- |
| 82b |
| piperazinyl)ethylidene-6,11-dihydrodibenz[b,e]oxepin- |
| 2-yl]propionic acid |
| 3-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl)- |
| 83b |
| ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11-[3-(4-Phenyl-1-piperidinyl)propylidene]-6,11- |
| 84b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11- |
| 85b |
| dihydrodibenz[b,e]oxepin-2-carboxylic acid |
| 11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11- |
| 86b |
| dihydrodibenz[b,e]oxepin-2-acetic acid |
| 2-Methyl-2-[11-[3-(4-benzyl-1-piperidinyl)- |
| 88b |
| propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-yl]- |
| propionic acid |
| 11-[3-[4-(4-Chlorobenzyl)-1-piperidinyl]propylidene]- |
| 90b |
| 6,11-dihydrodibenz[b,e]oxepin-2-acetic acid |
| 2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperidinyl)- |
| 91b |
| propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]- |
| propionic acid |
| 11-[3-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]- |
| 93b |
| propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic |
| acid |
| 11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]- |
| 98b |
| ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic |
| acid |
| 11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11- |
| 99b |
| dihydrodibenzo[b,e]thiepin-2-carboxylic acid |
| 11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11- |
| 100b |
| dihydrodibenzo[b,e]thiepin-2-carboxylic acid |
| 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11- |
| 101b |
| dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid |
| 5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]- |
| 102b |
| 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic |
| acid |
| 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo- |
| 103b |
| [a,d]cyclohepten-3-carboxylic acid |
| 5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]- |
| 104b |
| 5H-dibenzo[a,d]cyclohepten-3-carboxylic acid |
| ______________________________________ |
Next, TXA2 antagonizing activity of Compound (I) is described below.
Using guinea pig platelets influence of the compounds in accordance with the present invention on platelet aggregation induced by U-46619 (9,11-dideoxy-9α,11a-methanoepoxyprostaglandin F2 α; manufactured by Cayman Chemica Co., Ltd.) which is a TXA2 /prostaglandin H2 receptor stimulant was examined.
Male guinea pig (Hartley strain; body weight, 300 to 600 g) was anesthesized by intraperitoneal administration of sodium pentobarbital (30 mg/kg) and blood was collected from the descending aorta of the abdomen with a 1/10 volume of sodium citrate. By centrifugation (KC-70: manufactured by Kubota Co., Ltd.) at 800 rpm for 10 minutes, platelet rich plasma (PRP) was collected. Platelet aggregation induced by U-46619 (0.5-1 μM) was determined by photometry [Born, G.V.R. et al., Nature (London), 194, 927-929 (1962)]. A test compound was pretreated 3 minutes prior to aggregation induction and ability of inhibiting aggregation was measured. The minimum concentration for inhibiting platelet aggregation by 30% or more was defined as the minimum effective concentration (MEC) of the test compound.
The results are shown in Table 3.
Antiallergic activity was examined in accordance with the passive cutaneous anaphylaxis (PCA) test using rats. As test animals, Wistar strain male rats weighing 180 to 220 g were used to collect antiserum and for the PCA test, Wistar strain male rats weighing 120 to 140 g were used.
Anti-EWA rat serum was prepared according to the method of Stotland and Share [Can. J. Physiol. Pharmacol., 52, 1114 (1974)]. That is, 1 mg of EWA was mixed with 20 mg of aluminum hydroxide gel and 0.5 ml of pertussis-diphtberia-tetanus mixed vaccine. The mixture was subcutaneously administered to the rat paw in 4 portions. Fourteen days after, blood was collected from the carotid artery and the serum was isolated and stored in a state frozen at -80°C Titer of this antiserum to homologous PCA for 48 hours was 1:32.
Three rats were used per group. After the hair at the back was cut, 0.05 ml each of anti-EWA rat serum diluted to 8-fold with physiological saline was intracutaneously injected to each rat at the back in 2 places to passively sensitize the rat. A test compound or its solution (physiological saline solution or CMC solution) was orally administered 47 hours after and 0.5 ml/100 g of 1% Evans Blue physiological saline containing 2 mg of antigen EWA was then intravenously administered to the tail vein an hour after the administration. Thirty minutes later, the animal was bled to death. The skin was peeled off and a leaked dye amount at the blue dyed portion was measured according to the method of Katayama et al. [Microbiol. Immunol., 22, 89 (1978)]. That is, the blue dyed portion was cut off with scissors, put into a test tube charged with 1 ml of 1 N potassium hydroxide and incubated at 37°C for 24 hours. After 9 ml of a mixture of 0.6 N phosphate:acetone (5:13) was added to the system, the mixture was shaken followed by centrifugation at 2500 rpm for 10 minutes. The absorbancy of the supernatant at 620 nm was measured and the leaked dye amount was quantitatively determined by comparison with a calibration curve previously prepared. A value of one rat was obtained from a mean value of the two portions and an inhibition rate-of each rat was calculated according to the following equation. ##EQU1##
The case showing that the inhibition rate is 50% or more is judged to be positive in the PCA inhibition activity and the minimum dose in which at least one out of 3 rats was recognized to be positive was defined as the minimum effective dose (MED) of the test compound.
The results are shown in Table 3.
Using three dd strain male mice weighing 20±1 g, a test compound was orally (po; 300 mg/kg) or intraperitoneally (ip; 100 mg/kg) administered. MLD (the minimum lethal dose) was determined by observing the mortality for seven days after administration.
The results are shown in Table 3.
| TABLE 3 |
| ______________________________________ |
| Antiallergic |
| TXA2 |
| Acute Toxicity |
| Activity Antagonizing |
| Compound (MLD) mg/kg (MED) mg/kg Activity (MEC) |
| No.** po ip po μg/ml |
| ______________________________________ |
| 1b' >300 >100 10 3 |
| 8b >300 >100 10 1 |
| 9b' >300 >100 10 1 |
| 11b >300 >100 10 1 |
| 25b >300 >100 10 3 |
| 37b >300 >100 1 10 |
| 38b >300 >100 1 1 |
| E-73b >300 >100 >100 10 |
| E-75b' >300 >100 100 0.1 |
| E-78b >300 >100 >100 3 |
| E-79b >300 >100 >100 30 |
| BM13177* >300 >100 >100 3 |
| (reference |
| compound) |
| ______________________________________ |
| ##STR245## |
| **In Compound No., symbol ' indicates an addition product of the |
| corresponding compound in Tables 1 through 2 to a salt or solvent and, |
| symbols E and Z represents Eform and Zform, respectively (the same shall |
| apply hereinafter). |
As demonstrated in Table 3, Compound (I) and pharmaceutically acceptable salts thereof possess an excellent TXA2 antagonizing activity and some compounds also possess an antiallergic activity.
Receptor binding was determined by a modified method of Kattelman et al. (Thrombosis Research, 41, 471 (1986)].
To a washed platelet suspension (1×108 platelets) of guinea pig were added 12 nM of tritium-labeled U46619 (3 H-U46619; NEN Co., Ltd.) and a test compound (final concentration: 1 μM) solution. After keeping at 37°C for 20 minutes, the mixture was rapidly filtered through a glass fiber filter paper (GF/C; Whatman). Immediately, the filter paper was washed 5 times with 3 ml of ice-cold 50 mM Tris-hydroxymethylaminomethane buffer (containing 100 mM sodium chloride). The glass fiber filter was transferred to a vial and a scintillator (Ex-H; manufactured by Wako Pure Chemical Industries Co., Ltd.) was added thereto. The radioactivity was determined with a liquid scintillation counter.
It is already known that 3 H-U46619 is capable of binding with TXA2 receptor (see the publication supra). An inhibitory activity of the test compound against this binding means an ability of binding with the TXA2 receptor. It is also known that a good relationship exists between this binding activity and the anti-platelet activity (TXA2 antagonizing test).
An inhibitory activity (binding activity) of the test compound was calculated by the following equation. ##EQU2##
(Notes)
Amount of the total binding is an amount of 3 H-U46619-bound radioactivity in the absence of a test compound.
The amount of non-specific binding is used to mean an amount of 3 H-U46619-bound radioactivity in the presence of 10 μM U-46619.
The amount bound in the presence of a test compound is an amount of 3 H-U46619-bound radioactivity in the presence of a test compound in various concentrations.
The results are shown in Table 4.
| TABLE 4 |
| ______________________________________ |
| % Inhibition |
| ______________________________________ |
| Compound No. |
| 11b 70 |
| 25b 78 |
| 38b 81 |
| E-73b 85 |
| E-75b' 85 |
| E-78b 83 |
| E-79b 77 |
| Reference compounds: |
| Ketotifen -3 |
| Bm13177 31 |
| ##STR246## -4 |
| ##STR247## 1 |
| ______________________________________ |
As demonstrated in Table 4, Compound (I) and pharmaceutically acceptable salts thereof have an excellent binding ability to TXA2 receptor.
This inhibitory activity is not observed with hitherto known antiallergic agents, for example, Ketotifen [Merck Index, 10th edition, page 762 (1983)] and known antiallergic agents such as Compound (A) (Japanese Published Unexamined Patent Application No. 28972/1985) and Compound (B) (Japanese Published Unexamined Patent Application No. 10784/1988); one of excellent activity of Compound (I) is TXA2 receptor binding ability.
Receptor binding was determined by the method of chang et al. [J. Neurochem., 32, 1953 (1979)].
The cerebellum of guinea pig was suspended in a 40-fold amount (V/W) of chilled 50 mM phosphate buffer (pH 7.5) with Polytron Homogenizer (Kinematica Co., Ltd.). The suspension was centrifuged (35,500×g, 10 minutes). The resulting precipitates were resuspended in an equal amount of fresh buffer followed by centrifugation. A 100-fold amount (V/W) of chilled buffer was added to the final precipitates.
To 1 ml of the membrane suspension adjusted as described above were added 50 μl of tritium-labeled pyrilamine (3 H-pyrilamine; NEN Co., Ltd.) and 50 μl of a test compound. The mixture was allowed to stand at 25°C for 30 minutes, 4 ml of chilled buffer was added thereto. The mixture was rapidly filtered through a glass fiber filter (GF/C; Whatman). The filter paper was further washed three times with 5 ml of buffer. Hereafter procedures were performed in a manner similar to the TXA2 receptor binding test to determine radioactivity.
An inhibitory activity of the test compound against H1 receptor was calculated by the following equation. ##EQU3##
(Notes)
Amount of the total binding is an amount of 3 H-pyrilamine-bound radioactivity in the absence of a test compound.
The amount of non-specific binding is an amount of 3 H-pyrilamine-bound radioactivity in the presence of 3 μM Astemizole (manufactured by Janesen Pharmaceutics).
The amount bound in the presence of a test compound is an amount of 3 H-pyrilamine-bound radioactivity in the presence of a test compound in various concentrations.
Inhibitory activity of the test compounds at 10-6 M are shown in table 5.
| TABLE 5 |
| ______________________________________ |
| (%) Inhibition |
| ______________________________________ |
| Compound No. |
| 1b' 68 |
| 11b 95 |
| 25b 95 |
| 38b 92 |
| Reference Compounds: |
| Ketotifen 100 |
| BM13177 0 |
| Compound A 88 |
| ______________________________________ |
Compound (I) and pharmaceutically acceptable salts thereof may be administered alone but in general, it is preferably administered as combination medical preparation. These medical preparations are used for animal and human beings.
The medical preparation in accordance with the present invention may contain, as an active ingredient, Compound (I) or pharmaceutically acceptable salts thereof singly or as admixture with other optional effective components for different treatment. Further these medical preparations can be produced by optional procedures well known in the pharmaceutical field, by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.
Herein, as the optional effective components for different treatment combined with Compound (I) or pharmaceutically acceptable salts thereof, mention may be made of, for example, a steroid, a non-steroid antiinflammatory agent, a peripheral analgesic, a leucotriene antagonist, a leucotriene biosynthesis inhibitor, an H2 receptor antagonist, an antihistaminic agent, a histamine release inhibitor, a bronchodilator, an angiotensin converting enzyme inhibitor, a thromboxane A2 biosynthesis inhibitor, an H+ -K+ ATPase inhibitor, a coronary dilator, a calcium antagonist, a diuretic, a xanthine oxidase inhibitor, a cerebral circulation improving agent, a celebral metabolism activator, a cerebral protecting agent, a liver protecting agent, an antiplatelet agent, a thrombolytic agent, an adrenaline α receptor antagonist, an adrenergic β receptor agent, an adrenaline β receptor antagonist, a serotonine antagonist, a platelet activation factor (PAF) antagonist, an adenosine receptor antagonist, an antihyperlipidemic agent, a cholesterol biosynthesis inhibitor, an immunostimulating agent, an immunosuppressive agent, an anticancer agent, etc.
It is preferred that the most effective route for treatment be selected as a route for administration, oral or parenteral administration such as intrarectal, topical, intranasal, intraocular, intrabuccal, subcutaneous, intramuscular and intravenfus route etc.,,
As the form of administration preparations of the invention may be administered a capsule, a tablet, a granule, a powder, a syrup, an emulsion, a suppository, an ointment, an eyedrop, a nosedrop, a troche, an aerosol, an injection, etc.
A liquid preparation suited for oral administration, for example, an emulsion and a syrup can be prepared using water; sugars such as sucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol, propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil, etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavors such as strawberry flavor, pepper mint, etc. Further a capsule, a tablet, a powder and a granule, etc. can be prepared using an excipient such as lactose, glucose, sucrose, mannitol, etc.; a disintegrator such as starch, sodium alginate, etc.; a lubricant such as magnesium stearate, talc, etc.; a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc.; a surfactant such as an aliphatic ester, etc.; a plasticizer, such as glycerine, etc.
A preparation suited for parenteral administration is composed of a sterile aqueous preparation containing active compounds which are preferably isotonic to the blood of the recipient. For example, with an injection, a solution for injection is prepared using carriers composed of a saline solution, a glucose solution or a mixture of saline water and glucose solution.
A nasal spray preparation is composed of a purified aqueous solution of the active compounds which contains an antiseptic and an isotonic agent. Such a preparation is adjusted to pH compatible with the nasal membrane and to an isotonic state.
An ocular preparation is prepared in a manner similar to the nasal spray, except that pH and isotonic factors are controlled so as to fit those of eyes.
A topical preparation is prepared by dissolving or suspending the active compound in one or more media, for example, a mineral oil, petroleum, a polyvalent alcohol or other bases used for topical medical preparations.
A preparation for rectal administration is provided as a suppository using conventional carriers, for example, cacao fat, hydrogenated fat or hydrogenated fat carboxylic acid, etc.
Further these parenteral preparations may also be added with one or more auxiliary components such as a diluent, a fragrance, an antiseptic (including an antioxidant), an excipient, a disintegrator, a lubricant, a binder, a surfactant, a plasticizer and the like. YR)i
Effective dose and regimen of administration of Compound (I) or pharmaceutically acceptable salts thereof vary depending upon mode of administration, age and body weight of the patient and propertier or severity of conditions to be treated. In general, daily dose is 0.01 to 1,000 mg/person which may be administered as a single or divided doses.
Hereafter, the present invention is described by referring to Reference Examples and Examples below.
Intermediates obtained in the following Reference Examples are shown in Table 6.
| TABLE 6 |
| __________________________________________________________________________ |
| ##STR248## |
| Compound |
| (Reference |
| Example) |
| X1 X2 |
| Ro Xo |
| __________________________________________________________________________ |
| a (1) CH2 O |
| 2-COOCH3 |
| O |
| b (2) " " OH |
| c (3) " " CHCH2 Cl |
| d (4) " 2-CH2 COOCH3 |
| O |
| e (5) " " CHCH2 Cl |
| f (6) " 2-C(CH3)2 COOCH3 |
| O |
| g (7) " " OH |
| h (8) " 2-COOCH3 |
| ##STR249## |
| i (9) " " |
| ##STR250## |
| j (10) " " |
| ##STR251## |
| k (11) " " |
| ##STR252## |
| l (12) " 2-C(CH3)2 COOCH3 |
| ##STR253## |
| m (13) CH2 O |
| 2-C(CH3)2 COOCH3 |
| ##STR254## |
| n (14) " " |
| ##STR255## |
| o (15) CH2 CH2 |
| 2-COOCH3 |
| ##STR256## |
| p (16) " " |
| ##STR257## |
| q (17) CHCH " |
| ##STR258## |
| r (18) " " |
| ##STR259## |
| s (19) CH2 O |
| " |
| ##STR260## |
| t (20) " " CHCH2 CH2 OSO2 CH3 |
| u (21) " " |
| ##STR261## |
| __________________________________________________________________________ |
A mixture of 348.9 g of methyl p-hydroxybenzoate sodium salt, 402.4 g of phthalide and 200 g of sodium chloride was stirred at 150°C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 4 liters of 10% acetic acid aqueous solution were added thereto. The mixture was allowed to stand at room temperature overnight. After stirring at room temperature for 3 hours, crystals were recovered by filtration. To the crystals was added 6 liters of water. After stirring at room temperature for 30 minutes, the crystals were taken out by filtration. To the crystals was added 3 liters of toluene. The mixture was stirred at room temperature for an hour. The crystals were taken out by filtration and dried by heating under reduced pressure to give 393.9 g of 2-(4-methoxycarbonylphenoxy)methyl benzoate.
IR (KBr tablet, cm-1): 3400, 1700, 1610, 1260, 1235.
In 5.0 liters of methylene chloride was suspended 392.7 g of the thus obtained 2-(4-methoxycarbonylphenoxy)methyl benzoate and, 266.0 g of trifluoroacetic anhydride was added to the suspension. After stirring at room temperature for an hour, 19.4 g of boron trifluoride ethyl ether complex was added to the mixture followed by stirring at-room temperature for 2 hours. The reaction solution was poured into ice water. After fractionation, the organic phase was washed with a diluted sodium hydroxide aqueous solution and then with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was recrystallized from isopropyl ether to obtain 335.3 g of the objective compound as white crystals.
Melting point: 128°-129°C
| ______________________________________ |
| Elemental analysis: as C16 H12 O4 |
| C H |
| ______________________________________ |
| Found (%) 71.55 4.48 |
| Calcd. (%) 71.63 4.51 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 3.84(s, 3 H), 5.14(s, 2 H), 6.87-8.93(m, 7 H).
IR (KBr tablet, cm-1): 1710, 1650, 1610, 1250, 1010.
PAC Methyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound b)Compound a, 50 g, obtained in Reference Example 1 was suspended in 300 ml of methanol and 6.3 g of sodium borohydride was added to the suspension. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, 10 ml of acetic acid and 300 ml of water were added thereto followed by stirring for 30 minutes. Insoluble matters were taken out by filtration and washed with methanol and then with water. By drying with heating under reduced pressure, 40 g of the objective compound was obtained.
NMR (CDCl3, δ, ppm): 2.16(s, 6 H), 2.30-2.76(m, 4 H), 3.83(s, 3 H), 4.83 and 6.40(ABq, J=12.6 Hz, 2 H), 5.01(s, 1 H), 6.79-7.93(m, 7 H).
IR (neat, cm-1): 2950, 1710, 1240, 1015.
PAC Methyl (E)-11-(2-chloroethylidene)-6,11-dihydrodibenz-[b,e]oxepin -2-carboxylate (Compound c)4-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolved in 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid was dropwise added to the solution. After stirring at 60°C for 2 hours, a solution of 36 g of methyl 11-methylene-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylate in 600 ml of tetrachloroethane was dropwise added to the reaction mixture followed by stirring at 90°C for further 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 1. Then, the mixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 3 l of methylene chloride. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=5:5:1) to give 44 g of methyl 11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2- carboxylate as colorless oil.
MS (m/z): 378 (M+).
NMR (CDCl3, δ, ppm): 2.24(s, 3 H), 2.45(s, 8 H), 2.94-3.32(m, 2 H), 3.84(s, 3 H), 5.22(bs, 2 H), 5.85 and 6.22(t, J=6.8 Hz, 1 H), 6.66-8.07(m, 7 H).
E-form compound, 21.5 g, isolated from the Z/E mixture described above in a conventional manner and 23.5 g of sodium acetate were suspended in 250 ml of dichloroethane and, 27.1 ml of ethyl chloroformate was dropwise added to the suspension. After completion of the dropwise addition, the mixture was stirred at room temperature for an hour and the solvent was distilled off under reduced pressure. The residue was extracted with 400 ml of ethyl acetate. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropanol to give 14.3 g of the objective compound as white crystals.
Melting point: 134°-135°C
| ______________________________________ |
| Elemental analysis: as C18 H15 ClO3 |
| C H |
| ______________________________________ |
| Found (%) 68.55 4.77 |
| Calcd. (%) 68.68 4.80 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 3.90(s, 3 H), 4.16(d, J=8.1 Hz, 2 H), 4.88(bs, 1 H), 5.57(bs, 1 H), 6.31(t, J=8.1 Hz, 1 H), 6.79-8.04(m, 7 H).
PAC Methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound d)The corresponding starting material was used, treated in a manner similar to Reference Example 1 and recrystallized from methanol to give the objective compound as light yellow crystals.
Melting point: 75°-76°C
PAC Methyl (E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]-oxepin-2-acetate (Compound e)The corresponding starting material was used, treated in a manner similar to Reference Example 3 and recrystallized from isopropanol to give the objective compound as white crystals.
Melting point: 127°-128°C
| ______________________________________ |
| Elemental analysis: as C19 H17 ClO3 |
| C H |
| ______________________________________ |
| Found (%) 69.37 5.40 |
| Calcd. (%) 69.41 5.21 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 3.55(s, 2 H), 3.69(s, 3 H), 4.14 (d, J=8.1 Hz, 2H), 4.7-5.4(m, 2 H), 6.23(t, J=8.1 Hz, 1H), 6.74(d, J=8.1 Hz, 1 H), 6.95-7.4 (m, 6H).
IR (KBr tablet, cm-1): 1731, 1487, 1256, 1137, 1004.
PAC Methyl 2-methyl-2-[(11-oxo-6,11-dihydrodibenz[b,e]oxepin)-2-yl]propionate (Compound f)Compound d, 30 g, obtained in Reference Example 4 was suspended in 300 ml of dimethylformamide and 30 g of potassium hydroxide as powder and then 27 ml of methyl iodide were added to the suspension. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was extracted with 500 ml of ethyl acetate. The extract was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) for purification to give 3.6 g of the objective compound as colorless oil.
NMR (CDCl3, δ, ppm): 1.62(s, 6 H), 3.66(s, 3 H), 5.17 (s, 2 H), 7.01(d, J=8.8 Hz, 1 H), 7.2-7.9(m, 5 H), 8.22(d, J=2.6 Hz, 1 H).
IR (neat, cm-1): 2874, 1729, 1648, 1597, 1490, 1016.
PAC Methyl 2-methyl-2-[(11-hydroxy-6,11-dihydrodibenz[b,e]-oxepin)-2-yllpropionate (Compound g)The objective compound was obtained as colorless oil from Compound f obtained in Reference Example 6 in a manner similar to Reference Example 2.
NMR (CDCl3, δ, ppm): 1.56(s, 6 H), 3.62(s, 3 H), 4.97 and 5.90(ABq, J=13.1 Hz, 2 H), 5.61(s, 1 H), 6.87 (d, J=8.4 Hz, 1 H), 7.05-7.40(m, 6 H).
IR (neat, cm-1): 2974, 1728, 1497, 1010.
PAC Methyl 11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylate (Compound h)In 400 ml of methylene chloride was suspended 40.0 g of Compound b obtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, was added to the suspension followed by stirring at room temperature for an hour. Then, 10.7 ml of 2-mercap was added to the mixture followed by stirring for additional 4 hours. After 100 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from toluene to give 37.6 g of the objective compound as white crystals.
Melting point: 128°-130°C
| ______________________________________ |
| Elemental analysis: as C18 H18 O4 S |
| C H |
| ______________________________________ |
| Found (%) 65.26 5.55 |
| Calcd. (%) 65.43 5.49 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 2.66(dt, J=2.1, 6.0 Hz, 2 H), 3.69 (t, J=5.9 Hz, 211), 3.89(s, 3 H), 4.91 and 6.43(ABq, J=12.7 Hz, 2 H), 5.09(s, 1 H), 6.82-7.98(m, 7 H).
IR (KBr tablet, cm-1): 3420, 1708, 1683, 1610, 1437, 1318, 1008.
PAC Methyl 11-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylate (Compound i)Compound h, 20.0 g, obtained in Reference Example 8 was dissolved in 200 ml of dimethylformamide and, 12 ml of 2,4,6-cholidine and 4.0 g of lithium chloride were added to the solution. Under ice cooling, 5.4 ml of methanesulfonyl chloride was dropwise added to the mixture. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed successively with 1 N hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) and crystallized from hexane to give 20.8 g of the objective compound.
Melting point: 100°-102°C
| ______________________________________ |
| Elemental analysis: as C18 H17 ClO3 S |
| C H |
| ______________________________________ |
| Found (%) 61.77 4.80 |
| Calcd. (%) 61.97 4.91 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 2.54-3.62(m, 4 H), 3.84(s, 3 H), 5.04(s, 1 H), 4.87 and 6.37(ABq, J=13.2 Hz, 2 H), 6.76-8.12(m, 7 H)
IR (CHCl3, cm-1): 1714, 1611, 1322, 1295, 1132, 1008
PAC Methyl 11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound j)Compound i, 10.1 g, obtained in Reference Example 9 was dissolved in 150 ml of acetonitrile and, 14.6 g of sodium iodide was added to the solution. The mixture was heated under reflux for 5 hours. After allowing it to stand for cooling, the reaction mixture was extracted with ethyl acetate and the extract was washed twice with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) and further solidified with hexane to give 3.1 g of the objective compound as white solid.
Melting point: 111°-113°C
| ______________________________________ |
| Elemental analysis: as C18 H17 IO3 S |
| C H |
| ______________________________________ |
| Found (%) 49.08 3.71 |
| Calcd. (%) 49.10 3.89 |
| ______________________________________ |
NMR (CDCl3, δ, ppm): 2.68-3.22(m, 4 H), 3.88(s, 3 H), 5.09(s, 1 H), 4.91 and 6.37(ABq, J=13.2 Hz, 2 H), 6.78-8.08(m, 7 H).
IR (CHCl3, cm-1): 1714, 1611, 1295, 1120, 1008.
PAC Methyl [2-(1-piperazinyl)ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound k)Compound j, 7.0 g, obtained in Reference Example 10 and 6.8 g of piperazine were heated under reflux for 8 hours in 300 ml of ethanol. The solvent was distilled off under reduced pressure. 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 3 followed by washing with diethyl ether. Next, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 500 ml of ethyl acetate. After washing successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5.9 g of the objective compound as light yellow oil. The product was provided for the following reaction without further purification.
NMR (CDCl3, δ, ppm): 2.19-3.33(m, 12 H), 3.84(s, 3 H), 5.06(s, 1 H), 4.86 and 6.44(ABq, J=12.7 Hz, 2 H), 6.76-8.12(m, 7 H).
MS (m/Z): 402 (M+).
PAC Methyl 2-methyl-2-[11-(2-hydroxyethyl)thio-6,11-dihydro-dibenz[b,e]oxepin]-2-yl]p ropionate (Compound l)The objective compound was obtained as colorless oil in a manner similar to Reference Example 8 using Compound g obtained in Reference Example 7.
NMR (CDCl3, δ, ppm): 1.56(s, 6 H), 2.64(dt, J=2.2, 6.0 Hz, 2 H), 3.65(s, 3 H), 4.85 and 6.27(ABq, J=13.1 Hz, 2 H), 5.01(s, 1 H), 6.7-7.4(m, 7 H).
PAC Methyl 2-methyl-2-[[11-(2-chloroethyl)thio-6,11-dihydro-dibenz[b,e]oxepin]-2-yl]p ropionate (Compound m)The objective compound was obtained as colorless oil in a manner similar to Reference Example 9 using Compound l obtained in Reference Example 12.
NMR (CDCl3, δ, ppm): 1.57(s, 6 H), 2.6-2.9(m, 2 H), 3.2-3.4(m, 2 H), 3.65(s, 3 H), 4.85 and 6.23(ABq, J=13.1 Hz, 2 H), 5.04(s, 1 H), 6.7-7.4(m, 7 H).
PAC Methyl 2-methyl-2-[[11-(2-iodoethyl)thio-6,11-dihydro-dibenz[b,e]oxepin]-2-yl]pro pionate (Compound n)The objective compound was obtained as colorless oil in a manner similar to Reference Example 10 using Compound m obtained in Reference Example 13.
NMR (CDCl3, δ, ppm): 1.56(s, 6 H), 3.64(s, 3 H), 5.27 (s, 1 H)
PAC Methyl 5-(2-hydroxyethyl)thio-10,11-dihydro-5 H-dibenzo-[a,d]cyclohepten-3-carboxylate (Compound o)In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5 H-dibenzo[a,d]-cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.
Melting point: 107°-109°C
NMR (CDCl3, δ, ppm): 2.51-2.65(m 3 H), 2.75-3.03(m, 2 H), 3.56-3.98(m, 4 H), 3.87(s, 3 H), 5.16(s, 1 H), 7.14-7.25(m, 5 H), 7.82(dd, J=1.5, 7.9 Hz, 1 H), 7.91(s, 1 H).
PAC Methyl 5-(2-iodoethyl)thio-10,11-dihydro-5 H-dibenzo[a,d]-cyclohepten-3-carboxylate (Compound p)Compound o, 0.46 g, obtained in Reference Example 15 and 1.10 g of triphenyl phosphine were suspended in 9.2 ml of benzene. While stirring under ice cooling, 0.65 ml of diethyl azodicarboxylate was added to the suspension followed by stirring at room temperature for 10 minutes. Then, 0.26 ml of iodomethane was added to the mixture followed by stirring at room temperature for 30 minutes, After 10 ml of ethyl acetate and 10 ml of water were added thereto, the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 0.57 g of the objective compound as pale yellow oil.
NMR (CDCl3, δ, ppm): 2.70-3.08(m, 6 H), 3.63-3.81(m, 2 H), 3.89(s, 3 H), 5.17(s, 1 H), 7.17-7.32(m, 5 H), 7.84(dd, J=1.7, 7.8 Hz, 1 H), 7.92(s, 1 H).
PAC Methyl 5-(2-hydroxyethyl)thio-5 H-dibenzo[a,d]cyclohepten -3-carboxylate (Compound q)The corresponding starting material was used, treated in a manner similar to Reference Example 15 and recrystallized from toluene to give the objective compound as pale yellow crystals.
Melting point: 130°-132°C
NMR (CDCl3, δ, ppm): 2.30-2.50(m, 3 H), 3.51(t, J=6.2 Hz, 2 H), 3.89(s, 3 H), 5.31(s, 1 H), 7.00(s, 1 H), 7.02(s, 1 H), 7.09-7.41(m, 5 H), 7.91(dd, J=1.5, 7.9 Hz, 1 H), 8.01(s, 1 H).
PAC Methyl 5-(2-iodoethyl)thio-5 H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound r)Compound q obtained in Reference Example 17 was used and treated in a manner similar to Reference Example 16 to give the objective compound as pale yellow oil.
NMR (CDCl3, δ, ppm): 2.57-3.07(m, 4 H), 3.92(s, 3 H), 5.31(s, 1 H), 7.01(s, 1 H), 7.02(s, 111), 7.09-7.41 (m, 5 H), 7.91(dd, J=1.5, 7.9 Hz, 1 H), 8.01(s, 1 H).
PAC Methyl (E)-11-[2-(1-piperazinyl)ethyl]thio-6,11-dihydro-dibenz[b,e]oxepin-2-aceta te (Compound s)The objective compound was obtained as colorless oil from Compound c (E-form) obtained in Reference Example 3 in a manner similar to Reference Example 11.
NMR (CDCl3, δ, ppm): 1.95-3.0(m, 7 H), 3.10(d, J=7.0 Hz, 2 H), 3.83(s, 311), 4.75-5.5(m, 2 H), 6.20(t, J=7.0 Hz, 1 H), 6.71(d, J=8.5 Hz, 1 H), 6.95-7.45(m, 4 H), 7.73(dd, J=2.2, 8.5 HZ, 1 H), 7.99(d, J=2.2 Hz, 1 H).
PAC Methyl (E,Z)-11-[3-(methylsulfonyl)oxy]propylidene-6,11-dihydrodibenz[b,e]oxepin- 2-carboxylate (Compound t)[3-[(Tetrahydro-2 H-pyran-2-yl)oxy]propyl]triphenylphosphonium bromide, 40.0 g, was suspended in 250 ml of tetrahydrofuran. Under ice cooling in nitrogen atmosphere, 50 ml of n-butyl lithium/hexane solution (1.6 N) was dropwise added to the suspension. After stirring at room temperature for an hour, 15.0 g of Compound a obtained in Reference Example 1 was added thereto followed by stirring at room temperature for 12 hours. After 50 ml of water was added to the reaction mixture, the mixture was extracted with 1 l of ethyl acetate. After washing thrice with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 500 ml of dioxane and 200 ml of water and 1.0 g of p-toluenesulfonic acid were added to the solution followed by heating under reflux for an hour. The mixture was concentrated under reduced pressure and the obtained residue was extracted with 1 k of ethyl acetate. After washing successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the extract was dried over anhydorus sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; toluene:ethyl acetate=1:1) to give 9.8 g of methyl (E,Z)-11-(3-hydroxy)propylidene -6,11-dihydrodibenz[b,e]oxepin-2-carboxylate. A ratio of E/Z was approximately 3:7 by NMR.
The obtained product, 4.8 g, mainly composed of the Z-form and 10.0 g of p-toluenesulfonic acid were stirred in 250 ml of acetic acid at 100°C for 42 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 200 ml of methanol was added to the residue followed by heating under reflux for 3 hours. The solvent was distilled off and reduced pressure and the residue was extracted with 500 ml of ethyl acetate. After washing with saturated sodium bicarbonate aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to give 4.5 g of the product showing an E/Z ratio of about 1:1.
NMR (CDCl3, δ, ppm): 2.17-2.72(m, 2 H), 3.37-3.76(m, 2 H), 3.77(s, 3 H), 4.68-5.43(m, 1 H), 5.70(t, J=7.4 Hz, 1.5 H; Z form), 6.40(t, J=6.9 Hz, 1.5 H; E form), 6.52-8.12(m, 7 H).
The aforesaid product, 3.5 g, showing an E/Z ratio of about 1:1 was dissolved in 50 ml of pyridine and 1.7 ml of methanesulfonyl chloride was dropwise added under ice cooling. After stirring for an hour under ice cooling, the solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with 1N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 4.3 g of the objective compound as colorless oil.
NMR (CDCl3, δ, ppm): --SO2 CH3 ; 2.93(s, 1.5 H; E form), 3.00(s, 1.5 H; Z form).
This product was provided for use in the following reaction step without particular purification. A ratio of E/Z was about 1:1.
PAC Methyl 11-[2-(1-homopiperazinyl)ethyl]thio-6,11-dihydro-dibenz[b,e]oxepin-2-carbo xylate (Compound u)The objective compound was obtained as colorless oil in a manner similar to Reference Example 11, using Compound j obtained in Reference Example 10 and homopiperazine.
NMR (CDCl3, δ, ppm): 1.4-2.0(m, 2 H), 2.4-3.1(m, 12 H), 3.85(s, 3 H), 5.02(s, 1 H), 4.87 and 6.44(ABq, J=12.9 Hz, 2 H), 6.75-8.05(m, 7 H).
IR (neat, cm-1): 2928, 1716, 1610, 1249, 1118, 1007.
PAC Methyl 11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 1a)After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of 1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5 hours, the solvent was distilled 6,L3f under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=30:10:3). The resulting crude product was solidified with diethyl ether to give 3.1 g of the objective compound.
PAC Methyl 11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate.dihydrochloride (Compound 1a')Compound 1a, 1.2 g, obtained in Example 1 was dissolved in 200 ml of isopropanol and 2 ml of 6 N hydrochloric acid/isopropanol solution was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropanol to give 0.9 g of the objective compound.
In Examples 3 through 7 below, the objective compound was prepared using Compound j obtained in Reference Example 10 and the corresponding piperazine compound in a manner similar to Example 1.
Methyl 11-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 8a)
Methyl 11-[2-[4-(2-methoxyphenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 9a)
Methyl 11-[2-(4-benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 11a)
Methyl 11-[2-(4-piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin- 2-carboxylate (Compound 15a)
Methyl 11-[2-[4-(diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 16a)
In Examples 8 through 14 below, the objective compound was prepared using Compound j obtained in Reference Example 10 and the corresponding piperidine compound in a manner similar to Example 1.
Methyl 11-[2-(4-phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 37a)
Methyl 11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate (Compound 38a)
Methyl 11-[2-[4-[2(3 H)-benzimidazolon-1-yl]piperidino]-ethyl]thio -6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 47a)
Methyl 11-[2-(4-phenyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 50a)
Methyl 11-[2-(4-benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 51a)
Methyl 11-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl]-thio-6,11-dihydrodibenz[b, e]oxepin-2-carboxylate (Compound 53a)
PAC Methyl 11-[2-(1-phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl) ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 58a)In Examples 15 through 17 below, the objective compound was prepared using the corresponding starting material n, p or r and 4-benzylpiperidine in a manner similar to Example 1.
Methyl 2-methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b, e]oxepin-2-yl]propionate (Compound 41a)
Methyl 5-[2-(4-benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro -5 H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound 101a)
Methyl 5-[2-(4-benzyl-1-piperidinyl)ethyl]thio- 5 H-dibenzo-[a,d]cyclohepten -3-carboxylate (Compound 103a)
Methyl (E,Z)-11-[3-(4-benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]ox epin-2-carboxylate (Compound E/Z-85a)
The objective compound was prepared using Compound t obtained in Reference Example 20 and 4-benzylpiperidine in a manner similar to Example 1. A ratio of E/Z was 1:1.
In Examples 19 through 22 below, the objective compound was prepared using the corresponding starting material c or e and the corresponding piperazine or piperldine compound in a manner similar to Example 1.
Methyl (E)-11-[2-[4-(4-fluorophenyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound E-73a)
Methyl (E,Z)-11-[2-[4-(2-pyrimidyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound E/Z-76a)
Methyl (E)-11-[2-(4-benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetate (Compound E-96a)
Methyl (E)-11-[2-[4-[2(3 H)-benzimidazolon-1-yl]piperidino]-ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2-acetate (Compound E-98a)
Physicochemical properties of compounds obtained in Examples 1 through 22 are shown in Table 7-1. In Tables 7-1 to 7-5, symbol * in solvent for recrystallization means solidification by tritylation.
| TABLE 7-1 |
| __________________________________________________________________________ |
| MP (°C.) |
| Example [Solvent |
| No. for re- Elemental analysis |
| (%) |
| (Compound |
| Appear- |
| crystal- |
| NMR IR MS Upper column: found |
| No.) ance lization] |
| (solvent) δ, ppm |
| (method) cm-1 |
| m/z Lower column: |
| __________________________________________________________________________ |
| calcd. |
| 1 white 129-130 |
| (CDCl3) 2.30-3.34(m, 12H), 3.82 |
| (KBr tablet) |
| 474 (M+) |
| C28 H30 |
| N2 O3 S |
| (1a) crystal |
| [isopro- |
| (s, 1H), 5.03(s, 1H), 4.83&6.39 |
| 3450, 2948, C H N |
| panol] |
| (ABq, J=13.1Hz, 2H), 6.30-8.06 |
| 2826, 1711, 71.11 |
| 6.23 |
| 5.80 |
| (m, 12H) 1610, 1598, 70.86 |
| 6.37 |
| 5.90 |
| 1242 |
| 2 white 188 -- (KBr tablet) |
| -- C28 H32 |
| Cl2 N2 |
| O3 S |
| (1a') crystal |
| (dec.) 1714, 1599, C H N |
| [isopro- 1494, 1118, 61.75 |
| 6.21 |
| 5.15 |
| panol] 1006 61.42 |
| 5.89 |
| 5.12 |
| 3 yellow -- (CDCl3) 2.4-3.3(m, 12H), 3.81 |
| (CHCl3) |
| 492 (M+) |
| -- |
| (8a) amorphous (s, 3H), 3.83(s, 3H), 4.86&6.41 |
| 2824, 1713, |
| (ABq, J=11.7Hz, 2H), 5.03(s, 1H), |
| 1611, 1508, |
| 6.7-7.4(m, 8H), 7.67(dd, J=2.5, |
| 1294, 1132, |
| 8.5Hz, 1H), 7.88(d, J=2.5Hz, 1H) |
| 1120, 1005 |
| 4 colorless |
| -- (CDCl3) 2.4-3.3(m, 12H), 3.81 |
| (CHCl3) |
| 504 (M+) |
| -- |
| (9a) oil (s, 3H), 3.83(s, 3H), 4.85&6.44 |
| 2936, 2806, |
| (ABq, J=12.8Hz, 2H), 5.07(s, 1H), |
| 1708, 1610, |
| 6.7-7.4(m, 9H), 7.76(dd, J=2.3, |
| 1496, 1005 |
| 8.5Hz, 1H), 7.98(d, J=2.3Hz, 1H) |
| 5 colorless |
| -- (CDCl3) 2.05-2.65(m, 12H), 3.46 |
| (CHCl3) |
| 487 (M+) |
| -- |
| (11a) oil (s, 2H), 3.83(s, 3H), 4.86&6.45 |
| 2816, 1714, |
| (ABq, J=12.0Hz, 2H), 5.06(s, 1H), |
| 1611, 1120, |
| 6.98-7.44(m, 9H), 7.78(dd, J=2.2, |
| 1006 |
| 8.6Hz, 1H), 7.98(d, J=2.2Hz, 1H) |
| 6 colorless |
| -- (CDCl3) 2.25-2.75(m, 12H), 3.36 |
| (CHCl3) |
| 532 (M+) |
| -- |
| (15a) oil (s, 2H), 3.81(s, 3H), 4.82&6.40 |
| 1702, 1602, |
| (ABq, J=12.2Hz, 2H), 5.03(s, 1H), |
| 1296, 1121, |
| 5.85(s, 2H), 6.55-6.8(m, 3H), |
| 1004 |
| 6.82(d, J=4.6Hz, 1H), 7.1-7.35 |
| (m, 4H), 7.72(dd, J=2.5, 8.5Hz, |
| 1H), 7.93(d, J=2.5Hz, 1H) |
| 7 colorless |
| -- (CDCl3) 3.84(s, 3H), 4.20(s, |
| (CHCl3) |
| 564 (M+) |
| -- |
| (16a) oil 1H), 4.87&6.43(ABq, J=12.7Hz, |
| 1715, 1610, |
| 2H), 5.07(s, 1H), 6.84(d, J=8.6 |
| 1495, 1241, |
| Hz, 1H), 7.78(dd, J=2.2, 8.6Hz, |
| 1117, 1005 |
| 1H), 7.97(d, J=2.2Hz, 1H) |
| 8 colorless |
| -- (CDCl3) 1.5-3.2(m, 13H), 3.84 |
| (CHCl3) |
| 473 (M+) |
| -- |
| (37a) oil (s, 3H), 4.95&6.50(ABq, J=12.7 |
| 1719, 1609, |
| Hz, 2H), 5.14(s, 1H), 6.87(d, |
| 1496, 1247, |
| J=8.5Hz, 1H), 7.05-7.45(m, 9H), |
| 1128, 1009 |
| 7.81(dd, J=2.2, 8.5Hz, 1H), 8.03 |
| (d, J=2.2Hz, 1H) |
| 9 colorless |
| -- (CDCl3) 1.0-2.2(m, 7H), 2.2- 3.2 |
| (CHCl3) |
| 487 (M+) |
| -- |
| (38a) oil (m, 8H), 3.83(s, 3H), 4.85&6.41 |
| 2924, 1713, |
| (ABq, J=13.9Hz, 2H), 5.06(s, 1H), |
| 1611, 1295, |
| 6.8-7.4(m, 10H), 7.75(dd, J=2.0, |
| 1120, 1007 |
| 8.5Hz, 1H), 7.95(d, J=2.0Hz, 1H) |
| 10 colorless |
| -- (DMSO-d6) 1.5-3.0(m, 12H), 3.82 |
| (CHCl3) |
| 529 (M+) |
| -- |
| (47a) oil (s, 3H), 4.12(m, 1H), 5.08&6.31 |
| 1718, 1686, |
| (ABq, J=12.7Hz, 2H), 5.51(s, 1H), |
| 1251, 1119, |
| 6.91(d, J=8.6Hz, 1H), 6.95-7.5 |
| 1015 |
| (m, 8H), 7.75(dd, J=2.2, 8.6Hz, |
| 1H), 8.04(d, J=2.2Hz, 1H) |
| 11 colorless |
| -- (CDCl3) 3.87(s, 3H), 4.90&6.45 |
| (CHCl3) |
| 489 (M+) |
| -- |
| (50a) oil (ABq, J=12.9Hz, 2H), 5.09(s, 1H), |
| 1715, 1610, |
| 6.86(d, J=8.6Hz, 1H), 7.79(dd, |
| 1247, 1117, |
| J=2.2, 8.6Hz, 1H), 8.00(d, J= |
| 1005 |
| 2.2Hz, 1H) |
| 12 colorless |
| -- (CDCl3) 1.2-2.7(m, 12H), 2.73 |
| (neat) 503 (M+) |
| -- |
| (51a) oil (s, 2H), 3.86(s, 3H), 4.88&6.44 |
| 2916, 1696, |
| (ABq, J=12.7Hz, 2H), 5.06(s, 1H), |
| 1609, 1570, |
| 6.84(d, J=8.6Hz, 1H), 7.00-7.40 |
| 1491, 1113, |
| (m, 9H), 7.78(dd, J=2.2, 8.6Hz, |
| 1008 |
| 1H), 7.98(d, J=2.2Hz, 1H) |
| 13 colorless |
| -- (CDCl3) 1.80-3.50(m, 13H), 3.87 |
| (CHCl3) |
| 536 (M+) |
| -- |
| (53a) oil (s, 3H), 4.90&6.43(ABq, J=12.7 |
| 2954, 2930, |
| Hz, 2H), 5.09(s, 1H), 6.86(d, J= |
| 1715, 1293, |
| 8.6Hz, 1H), 7.20-7.35(m, 4H), |
| 1132, 1121 |
| 7.43(d, J=8.6Hz, 2H), 7.85(d, |
| J=8.6Hz, 2H), 7.70-7.95(m, 2H) |
| 14 colorless |
| -- (CDCl3) 1.6-1.8(m, 2H), 2.4-3.0 |
| (CHCl3) |
| 543 (M+) |
| -- |
| (58a) oil (m, 10H), 3.86(s, 3H), 4.72(s, |
| 2926, 1703, |
| 2H), 4.90&6.46(ABq, J=12.8Hz, |
| 1600, 1499, |
| 2H), 5.13(s, 1H), 6.6-7.4(m, |
| 1376, 1243, |
| 10H), 7.75(dd, J=2.0, 8.5H, 1H), |
| 1118, 1006 |
| 8.00(d, J=2.0Hz, 1H) |
| 15 colorless |
| -- (CDCl3) 1.1-2.9(m, 15H), 1.55(s, |
| (CHCl3) |
| 529 (M+) |
| -- |
| (41a) oil 6H), 3.61(s, 3H), 4.99(s, 1H), |
| 2922, 1726, |
| 4.80&6.29(ABq, J=13.0Hz, 2H), |
| 1496, 1265, |
| 6.7-7.35(m, 12H) 1147, 1124, |
| 1105, 1013, |
| 906 |
| 16 pale -- (CDCl3) 1.13-1.99(m, 9H), 2.35-2.99 |
| (CHCl3) |
| 485 (M+) |
| -- |
| (101a) yellow (m, 8H), 3.62-3.96(m, 2H), |
| 1717, 1301, |
| oil 3.83(s, 3H), 5.16(s, 1H), 6.95-7.30 |
| 1280, 1105 |
| (m, 10H), 7.80(dd, J=1.5, |
| 7.9Hz, 1H), 7.92(s, 1H) |
| 17 pale -- (CDCl3) 1.11-2.03(m, 9H), 2.35 |
| (CHCl3) |
| 483 (M+) |
| -- |
| (103a) yellow (s, 2H), 2.38-2.81(m, 4H), 3.90 |
| 1716, 1299, |
| oil (s, 3H), 5.29(s, 1H), 7.01(s, |
| 1279, 1110 |
| 1H), 7.02(s, 1H), 7.06-7.42(m, |
| 10H), 7.92(dd, J=1.1, 9.7Hz, 1H), |
| 7.99(s, 1H) |
| 18 colorless |
| -- (CDCl3) 0.8-2.0(m, 7H), 2.1-2.9 |
| (neat) 467 (M+) |
| -- |
| (E/Z-85a) |
| oil (m, 8H), 3.78(s, 3H), 5.18(bs, |
| 2916, 1718, |
| 2H), 5.65(t, J=7.0Hz; Z form), |
| 1604, 1118, |
| 5.99(t, J=7.0Hz; E form), 6.6-8.0 |
| 1004 |
| (m, 12H), 7.93(d, J=2.4Hz, 1H) |
| 19 colorless |
| -- (CDCl3) 2.3-3.4(m, 10H), 3.83 |
| (KBr tablet) |
| 458 (M+) |
| -- |
| (E-73a) |
| amorphous (s, 3H), 4.7-5.6(m, 2H), 6.25(t, |
| 1707, 1605, |
| J=5.5Hz, 1H), 6.6-7.5(m, 9H), |
| 1504, 1240, |
| 7.73(dd, J=2.2, 8.6Hz, 1H), 8.00 |
| 1002 |
| (d, J=2.2Hz, 1H) |
| 20 colorless |
| -- (CDCl3) 2.35-2.7(m, 4H), 3.0-3.35 |
| (KBr tablet) |
| 442 (M+) |
| -- |
| (E/Z-76a) |
| oil (m, 2H), 3.88(s, 3H), 3.65-4.0 |
| 1713, 1585, |
| (m, 4H), 4.6-5.6(m, 2H), 6.30 |
| 1357, 1244, |
| (t, J=6.8Hz; Z form), 6.45(t, J= |
| 1002 |
| 4.8Hz; E form), 6.79(d, J=8.6Hz, |
| 1H), 7.0-7.5(m, 5H), 7.78(dd, J= |
| 2.2, 8.6Hz, 1H), 8.05(d, J=2.2Hz, |
| 1H), 8.27(d, J=4.6Hz, 2H) |
| 21 colorless |
| -- (CDCl3) 1.0-3.2(m, 11H), 3.47 |
| (neat) 467 (M+) |
| -- |
| (E-96a) |
| oil (s, 2H), 3.61(s, 3H), 4.85-5.3 |
| 2918, 1735, |
| (m, 2H), 6.14(t, J=6.8Hz, 1H), |
| 1489, 1011 |
| 6.66(d, J=9Hz, 1H), 6.8-7.34(m, |
| 11H) |
| 22 colorless |
| -- (CDCl3) 1.35-3.35(m, 11H), 3.54 |
| (CHCl3) |
| 509 (M+) |
| -- |
| (E-98a) |
| oil (s, 2H), 3.68(s, 3H), 4.65-5.5 |
| 1689, 1486, |
| (m, 2H), 6.22(t, J=6.6Hz, 1H), |
| 1148, 1008 |
| 6.73(d, J=8.4Hz, 1H), 6.8-7.5 |
| (m, 10H) |
| __________________________________________________________________________ |
Compound 1a, 0.8 g, obtained in Example 1 was dissolved in a solvent mixture of 300 ml of methanol and 10 ml of water and, 80 mg of sodium hydroxide was added to the solution followed by heating under reflux for 4 hours. After allowing to cool, 4 N hydrochloric acid aqueous solution was added to the mixture to adjust pH to 7. The mixture was concentrated under reduced pressure. Precipitated crystals were taken by filtration. After washing with water, 0.7 g of the objective compound was obtained as white solid.
In Examples 24 through 30 below, the objective compound was precared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
11-[2-[4-(4-Fluorophenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid (Compound 8b)
11-[2-[4-(2-Methoxyphenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid (Compound 9b)
11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11-dihydro-dibenz [b,e]oxepin-2-carboxylic acid.monohydrate (Compound 11b')
11-[2-(4-Piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydro-dibenz [b,e]oxepin-2-carboxylic acid (Compound 15b)
11-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid (Compound 16b)
11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz -[b,e]oxepin-2-carboxylic acid∅5 hydrate (Compound 37b')
11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz -[b,e]oxepin-2-carboxylic acid (Compound 38b)
PAC Sodium 11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylate (Compound 38b')Compound 38b, 45 g, obtained in Example 30 was suspended in 500 ml of methanol and 5.3 g of sodium methoxide was added to the suspension followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure. The resulting crude product was solidified with hexane to give 47 g of the objective compound.
PAC 11-[2-[4-[2(3 H)-Benzimidazolon-1-yl]piperidino[ethyl]thio-6,11-dihydrodibenz[b,e]oxepin -2-carboxylic acid∅5.iso-propanol ∅5 hydrate (Compound 47b')The objective compound was prepared by hydrolyzing Compound 47a obtained in Example 10 in a manner similar to Example 23.
PAC Sodium 11-[2-[4-[2(3 H)-Benzimidazolon-1-yl]piperidino]-ethyl]thio-6,11-dihydrodibenz[b,e]oxepi n-2-carboxylate.2.5 hydrate (Compound 47b")Compound 47b' obtained in Example 32 was converted into the sodium salt in a manner similar to Example 31.
In Examples 34 through 38 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
11-[2-(4-Phenyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid∅75 hydrate (Compound 50b')
11-[2-(4-Benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid∅2 isopropanol (Compound 51b')
11-[2-[4-(4-Chlorobenzoyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid∅1 isopropanol∅5 hydrate (Compound 53b')
11-[2-(1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl) -ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid. 0.25 hydrate (Compound 58b')
2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-yl]propionate (Compound 41)
PAC 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro-5 H-dibenzo [a,d]cyclohepten-3-carboxylic acid∅5 fumarate (Compound 101b')Compound 101a, 0.33 g, obtained in Example 16 was hydrolyzed in a manner similar to Example 23 to give 0.3 g of the corresponding Compound 101b. This compound was dissolved in 50 ml of acetone and 80 mg of fumaric acid was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from isopropanol to prepare 0.14 g of the objective compound.
PAC 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5 H-dibenzo[a,d]-cyclohepten -3-carboxylic acid∅5 fumarate∅5 isopropanol (Compound 103b')The objective compound was prepared using Compound 103a obtained in Example 17 in a manner similar to Example 39.
PAC (E,Z)-11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid.1.5 hydrate (Compound 85b')The objective compound was prepared by hydrolyzing Compound E/Z-85a obtained in Example 18 in a manner similar to Example 23.
A ratio of E/Z was 38:62.
In Examples 42 and 43 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
(E)-11-[2-[4-(4-Fluorophenyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylic acid.isopropanol. monohydrate (Compound E-73b')
PAC (E,Z)-11-[2-[4-(2-Pyrimidyl)-1-piperazinyl)ethylidene]-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid (Compound E/Z-76b)A ratio of E/Z was 85:15.
PAC (E)-11-[2-(4-Benzyl-1-piperidinyl)ethylidene]-6,11-dihydro-dibenz [b,e]oxepin-2-acetic acid∅5 fumarate (Compound E-96b')Compound E-96a, 2.0 g, obtained in Example 21 was hydrolyzed in a manner similar to Example 23 to give 1.7 g of the corresponding Compound E-96b. This compound was dissolved in 200 ml of acetone and 0.43 g of fumaric acid was added to the solution followed by stirring at room temperature for an hour. The precipitated crystals were taken by filtration to give 1.5 g of the objective compound.
PAC (E)-11-[2-[4-[2(3 H)-Benzimidazolon-1-yl]piperidino]-ethylidene ]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. monohydrate (Compound E-98b')The objective compound was prepared by hydrolyzing Compound E-98a obtained in Example 22 in a manner similar to Example 23.
PAC Sodium (E)-11-[2-[4-[2(3 H)-benzimidazolon-1-yl]piperidino]-ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2-acetate (Compound E-98b")Compound E-98b' obtained in Example 45 was converted into the sodium salt in a manner similar to Example 31.
Physicochemical properties of the compounds obtained in Examples 23 through 46 are shown in Table 7-2.
| TABLE 7-2 |
| __________________________________________________________________________ |
| MP (°C.) |
| Example [Solvent |
| No. for re- Elemental analysis |
| (%) |
| (Compound |
| Appear- |
| crystal- |
| NMR IR MS Upper column: found |
| No.) ance lization] |
| (solvent) δ, ppm |
| (method) cm-1 |
| m/z Lower column: |
| __________________________________________________________________________ |
| calcd. |
| 23 white 215 (DMSO-d6) 2.50-3.83(m, 12H), |
| (KBr tablet) |
| 460 (M+) |
| C27 H28 |
| N2 O3 |
| S.H2 O |
| (1b') crystal |
| (dec.) |
| 5.08&6.23(ABq, J=12.5Hz, 2H), |
| 3400, 2936, C H N |
| [isopro- |
| 5.51(s, 1H), 6.79-8.04(m, 12H) |
| 2824, 1694, 67.39 |
| 6.06 |
| 5.59 |
| panol] 1599, 1232, 67.76 |
| 6.32 |
| 5.85 |
| 24 white 165-166 |
| (DMSO-d6) 2.3-2.8(m, 8H), 3.0-3.1 |
| (KBr tablet) |
| 478 (M+) |
| C27 H27 |
| FN2 O3 S |
| (8b) amorphous |
| (dec.) |
| (m, 4H), 5.05&6.28(ABq, J= |
| 3400, 1607, C H N |
| [isopro- |
| 12.6Hz, 2H), 5.45(s, 1H), 6.85-7.1 |
| 1509, 1384, 67.55 |
| 5.65 |
| 5.58 |
| panol]* |
| (m, 5H), 7.4-7.5(m, 4H), 7.71 |
| 1232 67.76 |
| 5.69 |
| 5.85 |
| (dd, J=2.2, 8.7Hz, 1H), 7.99(d, |
| J=2.2Hz, 1H) |
| 25 white 171-175 |
| (DMSO-d6) 3.0-3.7(m, 12H), 3.81 |
| (KBr tablet) |
| 490 (M+) |
| C28 H30 |
| N2 O4 S |
| (9b) amorphous |
| [isopro- |
| (s, 3H), 5.10&6.16(ABq, J=12.9 |
| 1694, 1609, C H N |
| panol]* |
| Hz, 2H), 5.54(s, 1H), 6.90(d, |
| 1499, 1455, 68.23 |
| 6.35 |
| 5.88 |
| J=8.5Hz, 1H), 6.9-7.1(m, 4H), |
| 1200, 1115, 68.55 |
| 6.16 |
| 5.71 |
| 7.4-7.65(m, 4H), 7.74(dd, J=2.2, |
| 1013 |
| 8.5Hz, 1H), 8.06(d, J=2.2Hz, 1H) |
| 26 white 112-115 |
| (DMSO-d6) 2.2-2.7(m, 12H), 3.42 |
| (KBr tablet) |
| 474 (M+) |
| C28 H30 |
| N2 O3 |
| S.H2 O |
| (11b') crystal |
| (dec.) |
| (s, 2H), 5.01&6.24(ABq, J=12.7 |
| 3400, 1609, C H N |
| [iso- Hz, 2H), 5.39(s, 1H), 6.81(d, J= |
| 1384, 1232, 68.33 |
| 6.25 |
| 5.54 |
| propyl |
| 8.6Hz, 1H), 7.2-7.5(m, 9H), 7.69 |
| 1008 68.27 |
| 6.55 |
| 5.69 |
| ether] |
| (dd, J=2.2, 8.6Hz, 1H), 7.95(d, |
| 2.2Hz, 1H) |
| 27 white 218-220 |
| (DMSO-d6) 2.2-2.7(m, 12H), 3.34 |
| (KBr tablet) |
| 518 (M+) |
| C29 H30 |
| N2 O5 S |
| (15b) crystal |
| (dec.) |
| (s, 2H), 5.04&6.26(ABq, J=12.7 |
| 1670, 1609, C H N |
| [isopro- |
| Hz, 2H), 5.43(s, 1H), 5.98(s, |
| 1491, 1242, 67.09 |
| 5.95 |
| 5.24 |
| panol] |
| 2H), 6.72(d, J=7.9Hz, 1H), 6.8-6.85 |
| 1040 67.16 |
| 5.83 |
| 5.40 |
| (m, 2H), 6.86(d, J=8.6Hz, |
| 1H), 7.35-7.5(m, 4H), 7.71(dd, |
| J=2.2, 8.6Hz, 1H), 7.98(d, J= |
| 2.2Hz, 1H) |
| 28 white 145-148 |
| (DMSO-d6) 2.2-2.7(m, 12H), 4.26 |
| (KBr tablet) |
| 550 (M+) |
| C34 H34 |
| N2 O3 S |
| (16b) crystal |
| [isopro- |
| (s, 1H), 5.04&6.23(ABq, J=12.6 |
| 1683, 1608, C H N |
| panol] |
| Hz, 2H), 5.44(s, 1H), 6.86(d, |
| 1493, 1451, 73.98 |
| 6.35 |
| 5.00 |
| J=8.6Hz, 1H), 7.70(dd, J=2.2, |
| 1232, 1006 74.15 |
| 6.22 |
| 5.09 |
| 8.6Hz, 1H), 7.98(d, J=2.2Hz, 1H) |
| 29 white 182-184 |
| (DMSO-d6) 1.65-3.0(m, 13H), 5.06 |
| (KBr tablet) |
| 459 (M+) |
| C28 H29 |
| NO3 S∅5H2 |
| O |
| (37b') crystal |
| [isopro- |
| &6.27(ABq, J=12.7Hz, 2H), 5.48 |
| 1680, 1605 C H N |
| panol] |
| (s, 1H), 6.88(d, J=8.5Hz, 1H), |
| 1494, 1318, 71.85 |
| 6.23 |
| 2.98 |
| 7.15-7.5(m, 9H), 7.72(dd, J=2.2, |
| 1233, 1104, 71.77 |
| 6.45 |
| 2.99 |
| 8.5Hz, 1H), 8.01(d, J=2.2Hz, 1H) |
| 1007 |
| 30 white 205-206 |
| (DMSO-d6) 1.0-1.9(m, 7H), 2.2-2.85 |
| (KBr tablet) |
| 473 (M+) |
| C26 H31 |
| NO3 S |
| (38b) crystal |
| [isopro- |
| (m, 8H), 5.03&6.25(ABq, J= |
| 2912, 1687, C H N |
| panol] |
| 12.6Hz, 2H), 5.42(s, 1H), 6.86 |
| 1608, 1494, 73.48 |
| 6.72 |
| 2.92 |
| (d, J=8.6Hz, 1H), 7.1-7.5(m, 9H), |
| 1449, 1323, 73.54 |
| 6.60 |
| 2.96 |
| 7.70(dd, J=2.2, 8.6Hz, 1H), 7.97 |
| 1229, 1019 |
| (d, J=2.2Hz, 1H) |
| 31 white 119-121 |
| -- (KBr tablet) |
| -- C29 H30 |
| NO3 SNa∅5H2 |
| O |
| (38b') solid [hexane]* 2918, 1612, C H N |
| 1582, 1548, 68.80 |
| 6.44 |
| 2.93 |
| 1385, 1252, 69.03 |
| 6.19 |
| 2.78 |
| 1227, 1105, |
| 1011 |
| 32 white 185-188 |
| (DMSO-d6) 1.55-3.1(m, 12H), |
| (KBr tablet) |
| 515 (M+) |
| C29 H29 |
| N3 O4 |
| S∅5C3 H8 |
| O. |
| (47b') crystal |
| [aceto- |
| 4.14(m, 1H), 5.07&6.28(ABq, J= |
| 1695, 1485, 0.5C2 H3 N |
| nitrile/ |
| 12.7Hz, 2H), 5.48(s, 1H), 6.89 |
| 1386 C H N |
| isopro- |
| (d, J=8.6Hz, 1H), 6.95-7.5(m, 66.41 |
| 5.90 |
| 8.45 |
| panol] |
| 8H), 7.72(dd, J=2.2, 8.6Hz, 1H), |
| 66.75 |
| 6.22 |
| 8.57 |
| 8.06(d, J=2.2Hz, 1H), 10.83(s, |
| 1H) |
| 33 white 224-227 |
| -- (KBr tablet) |
| -- C29 H28 |
| N3 O4 |
| SNa.2.5H2 O |
| (47b") crystal |
| [methanol] 1683, 1583, C H N |
| 1543, 1485, 59.77 |
| 5.72 |
| 7.10 |
| 1379, 1256, 59.78 |
| 5.71 |
| 7.21 |
| 1229, 1109, |
| 1006 |
| 34 white 150-154 |
| (DMSO-d6) 1.5-1.6(m, 2H), 1.8-2.0 |
| (KBr tablet) |
| 475 (M+) |
| C28 H29 |
| NO4 S∅75H2 |
| O |
| (50b') crystal |
| [isopro- |
| (m, 2H), 2.35-2.75(m, 8H), |
| 1611, 1584, C H N |
| panol] |
| 5.05&6.28(ABq, J=12.7Hz, 2H), |
| 1550, 1375, 68.60 |
| 6.41 |
| 2.88 |
| 6.87(d, J=8.5Hz, 1H), 7.15-7.5 |
| 1228, 1006 68.76 |
| 6.29 |
| 2.86 |
| (m, 9H), 7.71(dd, J=2.1, 8.5Hz, |
| 1H), 8.01(d, J=2.1Hz, 1H) |
| 35 white 232 (DMSO-d6) 1.25-1.5(m, 4H), 2.2-2.75 |
| (KBr tablet) |
| 489 (M+) |
| C29 H31 |
| NO4 S∅2C3 |
| H8 O |
| (51b') crystal |
| [isopro- |
| (m, 8H), 2.63(s, 2H), 5.02& |
| 1608, 1492, C H N |
| panol] |
| 6.25(ABq, J=12.6Hz, 2H), 5.41(s, |
| 1383, 1232, 70.98 |
| 6.43 |
| 2.49 |
| 1H), 6.85(d, J=8.6Hz, 1H), 7.15-7.45 |
| 1107, 1009 70.87 |
| 6.55 |
| 2.79 |
| (m, 9H), 7.70(dd, J=2.2, 8.6 |
| Hz, 1H), 7.96(d, J=2.2Hz, 1H) |
| 36 pale 138-139 |
| (DMSO-d6) 1.4-3.5(m, 13H), 5.05 |
| (KBr tablet) |
| 522 (M+) |
| C29 H28 |
| ClNO4 S∅1 |
| (53b') yellow |
| [iso- &6.27(ABq, J=12.6Hz, 2H), 5.46 |
| 1676, 1608, C6 H14 |
| O∅5H2 O |
| solid propyl |
| (s, 1H), 6.87(d, J=8.6Hz, 1H), |
| 1587, 1376, C H N |
| ether]* |
| 7.35-7.5(m, 4H), 7.59(d, J=8.6Hz, |
| 1229, 1091, 65.81 |
| 5.39 |
| 2.22 |
| 2H), 7.71(dd, J=2.1, 8.6Hz, 1H), |
| 1009 65.46 |
| 5.68 |
| 2.58 |
| 7.97(d, J=8.6Hz, 2H), 7.99(d, |
| J=2.1Hz, 1H) |
| 37 white 186-189 |
| (DMSO-d6) 1.56(d, J=13.6Hz, 2H), |
| (KBr tablet) |
| 529 (M+) |
| C30 H31 |
| N3 O4 |
| S∅25H2 O |
| (58b') solid [isopro- |
| 2.4-2.9(m, 10H), 4.57(s, 2H), |
| 1710, 1598, C H N |
| panol] |
| 5.06&6.26(ABq, J=12.6Hz, 2H), |
| 1497, 1379, 67.29 |
| 5.82 |
| 7.69 |
| 5.54(s, 1H), 6.75-7.2(m, 5H), |
| 1105, 1009 67.46 |
| 5.94 |
| 7.87 |
| 6.88(d, J=8.5Hz, 1H), 7.72(dd, |
| J=2.1, 8.5Hz, 1H), 8.04(d, J= |
| 2.1Hz, 1H), 8.64(s, 1H) |
| 38 white 84-86 (DMSO-d6) 1.1-1.3(m, 2H), 1.35-1.6 |
| (KBr tablet) |
| 515 (M+) |
| C32 H37 |
| NO3 S |
| (41b) solid [water]* |
| (m, 3H), 1.43&1.45(each s, |
| 2926, 1720, C H N |
| 6H), 1.85-2.0(m, 2H), 2.35-2.9 |
| 1496, 1453, 74.21 |
| 7.45 |
| 2.66 |
| (m, 8H), 5.33(s, 1H), 4.91&6.13 |
| 1231, 1123, 74.53 |
| 7.23 |
| 2.72 |
| (ABq, J=12.8Hz, 2H), 6.76(d, J= |
| 1014 |
| 8.4Hz, 1H), 7.1-7.45(m, 11H) |
| 39 pale 127-130 |
| (CD3 OD) 1.20-1.86(m, 5H), 2.35-3.20 |
| (KBr tablet) |
| 469 (M+) |
| C30 H31 |
| NO2 S∅5C4 |
| H4 O4 |
| (101b') |
| yellow |
| [isopro- |
| (m, 12H), 3.56-3.94(m, 2H), |
| 3420, 2920, C H N |
| crystal |
| panol] |
| 5.21(s, 1H), 7.03-7.33(m, 10H), |
| 1695, 1585, 72.60 |
| 6.60 |
| 2.55 |
| 7.75-7.86(m, 2H) 1453, 1372, 72.84 |
| 6.30 |
| 2.65 |
| 1244 |
| 40 pale 100-115 |
| (DMSO-d6) 1.18-2.11(m, 5H), 2.26-2.60 |
| (KBr tablet) |
| 467 (M+) |
| C30 H29 |
| NO2 S∅5C4 |
| H4 O4. |
| (103b') |
| yellow |
| (dec.) |
| (m, 8H), 2.63-2.92(m, 2H), |
| 3400, 2922, 0.5C3 H8 O |
| crystal |
| [isopro- |
| 5.44(s, 1H), 6.99(s, 2H), 7.01-7.49 |
| 1698, 1582, C H N |
| panol] |
| (m, 10H), 7.84(dd, J=1.3, |
| 1372 72.23 |
| 6.51 |
| 2.41 |
| 9.0Hz, 1H), 8.02(s, 1H) 72.41 |
| 6.35 |
| 2.52 |
| 41 white 146-149 |
| (DMSO-d6) 5.70(t, J=6.7Hz; Z |
| (KBr tablet) |
| 453 (M+) |
| C30 H31 |
| NO3.1.5H2 O |
| (E/Z-85b') |
| solid [water]* |
| form), 6.06(t, J=7.5Hz; E form), |
| 2920, 1605, C H N |
| 6.80(d, J=8.4Hz; E form), 6.88 |
| 1486, 1454, 75.09 |
| 7.22 |
| 2.82 |
| (d, J=8.6Hz; Z form), 7.76(d, J= |
| 1367, 1242, 74.97 |
| 7.13 |
| 2.91 |
| 2.2Hz; Z form), 7.87(d, J=2.0Hz; |
| 1004 |
| E form) |
| 42 white 236-238 |
| (DMSO-d6) 2.4-3.7(m, 10H), 4.95-5.65 |
| (KBr tablet) |
| 444 (M+) |
| C27 H25 |
| FN2 O3.C |
| 3 H8 O. |
| (E-73b') |
| crystal |
| (dec.) |
| (m, 2H), 6.17(t, J=6.7Hz, |
| 1608, 1509, H2 O |
| [isopro- |
| 1H), 6.83(d, J=8.5Hz, 1H), 6.85-7.55 |
| 1370, 1224 C H N |
| panol] |
| (m, 8H), 7.72(dd, J=2.2, 69.10 |
| 6.60 |
| 5.33 |
| 8.5Hz, 1H), 7.92(d, J=2.2Hz, 1H) |
| 68.95 |
| 6.75 |
| 5.36 |
| 43 pale 161-165 |
| (DMSO-d6) 2.3-3.8(m, 10H), 4.9-5.65 |
| (KBr tablet) |
| 428 (M+) |
| C25 H24 |
| N4 O3 |
| (E/Z-76b) |
| yellow |
| [isopro- |
| (m, 2H), 5.86(t, J=7.1Hz; Z |
| 1584, 1551, C H N |
| crystal |
| panol] |
| form), 6.18(t, J=6.6Hz; E form), |
| 1487, 1450, 69.91 |
| 5.78 |
| 13.22 |
| 6.6-8.4(m, 10H) 1360 70.08 |
| 5.65 |
| 13.08 |
| 44 white 203-204.5 |
| (DMSO-d6) 1.1-2.55(m, 9H), 2.46 |
| (KBr tablet) |
| 453 (M+) |
| C30 H31 |
| NO3∅5C4 |
| H4 O4 |
| (E-96b') |
| solid [acetone]* |
| (d, J=6.6Hz, 2H), 2.92(d, J=6.6 |
| 1704, 1488, C H N |
| Hz, 1H), 3.48(s, 2H), 4.0-5.5(m, |
| 1357, 1249, 74.92 |
| 6.64 |
| 2.79 |
| 2H), 6.08(t, J=6.6Hz, 1H), 6.57 |
| 1227, 1003 75.12 |
| 6.50 |
| 2.74 |
| (s, 1H), 6.67(d, J=8.4Hz, 1H), |
| 7.0-7.5(m, 11H) |
| 45 white 260-262 |
| (DMSO-d6) 1.5-3.6(m, 10H), 3.51 |
| (KBr tablet) |
| 495 (M+) |
| C30 H29 |
| N3 O4.H2 |
| O |
| (E-98b') |
| solid [isopro- |
| (s, 2H), 4.05-4.2(m, 1H), 4.93& |
| 1699, 1489, C H N |
| panol]* |
| 5.40(each bs, 2H), 6.13(t, J=6.7 |
| 1386, 1003 70.31 |
| 6.45 |
| 8.35 |
| Hz, 1H), 6.68(d, J=8.5Hz, 1H), 70.16 |
| 6.08 |
| 8.18 |
| 6.95-7.5(m, 10H) |
| 46 white 218-219.5 |
| (DMSO-d6) 1.5-2.5(m, 4H), 2.9-3.4 |
| (KBr tablet) |
| -- C30 H28 |
| N3 O4 Na |
| (E-98b") |
| crystal |
| [isopro- |
| (m, 6H), 3.15(s, 2H), 4.0-4.15 |
| 1681, 1567, C H N |
| panol] |
| (m, 1H), 4.2-5.6(m, 2H), 6.10(t, |
| 1485, 1381, 69.66 |
| 5.52 |
| 8.22 |
| J=6.7Hz, 1H), 6.57(d, J=8.3Hz, |
| 1009 69.62 |
| 5.45 |
| 8.12 |
| 1H), 6.9-7.5(m, 10H), 8.29(s, 1H) |
| __________________________________________________________________________ |
Compound k, 2.0 g, obtained in Reference Example 11 and 1.2 g of cinnamyl bromide were stirred in 100 ml of isopropanol for 4 hours at room temperature. The mixture was extracted with 300 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodi=chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=10:10:1) to give 0.8 g of the objective compound as pale yellow oil.
PAC Methyl (E)-11-[3-(4-cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxe pin-2-carboxylate (Compound E-75a)The objective compound was prepared using Compound s obtained in Reference Example 19 and cinnamyl bromide in a manner similar to Example 47.
In Examples 49 and 50 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives and then converting the hydrolyzate into the fumarate in a manner similar to Example 44.
11-[2-(4-Cinnamyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz [b,e]oxepin-2-carboxylic acid.difumarate∅5 hydrate (Compound 20b')
PAC (E)-11-[3-(4-Cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2-carboxylic acid.difumarate-0.5 hydrate (Compound E-75b')Physicochemical properties of the compounds obtained in Examples 47 to 50 are shown in Table 7-3.
| TABLE 7-3 |
| __________________________________________________________________________ |
| MP (°C.) |
| Example [Solvent |
| No. for re- Elemental analysis |
| (%) |
| (Compound |
| Appear- |
| crystal- |
| NMR IR MS Upper column: found |
| No.) ance lization] |
| (solvent) δ, ppm |
| (method) cm-1 |
| m/z Lower column: |
| __________________________________________________________________________ |
| calcd. |
| 47 pale -- (CDCl3) 2.32-2.80(m, 12H), 3.14 |
| (neat) 514 (M+) |
| -- |
| (20a) yellow (d, J=5.6Hz, 2H), 3.89(s, 3H), |
| 2944, 2808, |
| oil 4.89&6.45(ABq, J=14.5Hz, 2H), |
| 1708, 1610, |
| 5.10(s, 1H), 6.21-8.10(m, 14H) |
| 1571, 1497, |
| 1007 |
| 48 colorless |
| -- (CDCl3) 2.48(m, 8H), 3.0-3.3(m, |
| (neat) 480 (M+) |
| -- |
| (E-75a) |
| oil 4H), 3.81(s, 3H), 4.9-5.7(m, 2H), |
| 1715, 1606, |
| 6.05-6.5(m, 2H), 6.71(d, J=9.2Hz, |
| 1245, 1006 |
| 1H), 7.0-7.5(m, J=9.2Hz, 9H), |
| 7.73(dd, J=2.2, 9.2Hz, 1H), 7.99 |
| (d, J=2.2Hz, 1H) |
| 49 yellow |
| 210-211 |
| (DMSO-d6) 2.35-2.7(m, 12H), 3.25 |
| (KBr tablet) |
| 500 (M+) |
| C38 H40 |
| N2 O11 |
| S∅5H2 O |
| (20b') solid |
| [aceto- |
| (d, J=6.6Hz, 2H), 5.05&6.25(ABq, |
| 1713, 1612, C H N |
| nitrile]* |
| J=10.6Hz, 2H), 5.44(s, 1H), 6.25-6.3 |
| 1300, 1252, 61.48 |
| 5.42 |
| 3.88 |
| (m, 1H), 6.87(d, J=8.5Hz, 1H), |
| 1170 61.53 |
| 5.57 |
| 3.78 |
| 7.2-7.5(m, 10H), 7.71(dd, J=2.2, |
| 8.5Hz, 1H), 7.98(d, J=2.2Hz, 1H) |
| 50 white |
| 246 (DMSO-d6) 2.4-3.3(m, 10H), 3.24 |
| (KBr tablet) |
| 466 (M+) |
| C38 H38 |
| N2 O11∅5H.s |
| ub.2 O |
| (E-75b') |
| crystal |
| (dec.) |
| (d, J=6.7Hz, 2H), 4.9-5.7(m, 2H), |
| 1703, 1659, C H N |
| [aceto- |
| 6.14(t, J=6.7Hz, 1H), 6.2-6.35 |
| 1605, 1250, 64.53 |
| 5.43 |
| 4.05 |
| nitrile] |
| (m, 1H), 6.82(d, J=8.5Hz, 1H), |
| 1010, 980 64.49 |
| 5.55 |
| 3.96 |
| 7.2-7.55(m, 10H), 7.72(dd, J= |
| 2.2, 8.5Hz, 1H), 7.90(d, J=2.2Hz, |
| 1H) |
| __________________________________________________________________________ |
Compound k, 0.8 g, obtained in Reference Example 11 was dissolved in 50 ml of pyridine and 0.5 g of 4-fluorobenzenesulfonyl chloride was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=50:20:1) to give 0.6 g of the crude product. The crude product obtained was recrystallized from isopropyl ether to give 0.4 g of the objective compound.
In Examples 52 and 53 below, the objective compound was prepared using Compound k and the corresponding sulfonyl chloride compound in a manner similar to Example 51.
Methyl 11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethyl]thio -6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 24a)
PAC Methyl 11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethyl]-thio-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound 25a)In Examples 54 and 55 below, the objective compound was prepared using Compound k and the corresponding acid chloride compound in a manner similar to Example 51.
Methyl 11-[2-[4-(2,3,4-trimethoxybenzoyl)-1-piperazinyl]-ethyl]thio-6,11-dihydrod ibenz[b,e]oxepin-2-carboxylate (Compound 27a)
Methyl 11-[2-[4-(cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepi n-2-carboxylate (Compound 28a)
PAC Methyl 11-[2-[4-(phenoxycarbonyl)-1-piperazinyl]ethyl]thio -6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 30a)Compound k, 2.0 g, obtained in Reference Example 11 was dissolved in 100 ml of isopropanol and 0.75 ml of phenyl chloroformate was added to the solution followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=50:30:1) to give 1.7 g of the crude product. The crude product obtained was solidified with isopropyl ether to give 1.6 g of the objective compound.
PAC Methyl 11-[2-[4-(benzyloxycarbonyl)-1-piperazinyl]ethyl]-thio-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound 31a)The objective compound was prepared using Compound k and benzyl chloroformate in a manner similar to Example 56.
In Examples 58 and 59 below, the objective compound was prepared from Compound s obtained in Reference Example 19 and the corresponding sulfonyl chloride compound in a manner similar to Example 51.
Methyl (E)-11-[2-[4-(styrylsulfonyl)-1-piperazinyl]-ethylidene]-6,11-dihydrodiben z[b,e]oxepin-2-carboxylic acid (Compound E-78a)
Methyl (E)-11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]-ethylidene]-6,11-dihydrodi benz[b,e]oxepin-2-carboxylic acid (Compound E-79a)
PAC Methyl 11-[2-[4-(1-naphthalenesulfonyl)-1-homopiperazinyl]-ethyl]thio-6,11-dihydr odibenz[b,e]oxepin-2-carboxylate (Compound 34a)The objective compound was prepared using 1.4 g of Compound u obtained in Reference Example 21 and 1.0 g of 1-naphthalenesulfonyl chloride in a manner similar to Example 51.
Physicochemical properties of the compounds obtained in Examples 51 to 60 are shown in Table 7-4.
| TABLE 7-4 |
| __________________________________________________________________________ |
| MP (°C.) |
| Example [Solvent |
| No. for re- Elemental analysis |
| (%) |
| (Compound |
| Appear- |
| crystal- |
| NMR IR MS Upper column: found |
| No.) ance lization] |
| (solvent) δ, ppm |
| (method) cm-1 |
| m/z Lower column: |
| __________________________________________________________________________ |
| calcd. |
| 51 yellow |
| 80-82 (CDCl3) 2.25-3.15(m, 12H), 3.80 |
| (KBr tablet) |
| 556 (M+) |
| C28 H29 |
| FN2 O5 |
| S2 |
| (22a) amorphous |
| [iso- (s, 3H), 4.85&6.39(ABq, J=13.6 |
| 1702, 1494, C H N |
| propyl |
| Hz, 2H), 5.00(s, 1H), 6.77(d, J= |
| 1357, 1326, 60.60 |
| 5.39 |
| 4.88 |
| ether]* |
| 8.6Hz, 1H), 6.95-8.0(m, 10H) |
| 1244, 1172, 60.41 |
| 5.25 |
| 5.03 |
| 1004 |
| 52 colorless |
| -- (CDCl3) 2.4-2.75(m, 8H), 3.15-3.35 |
| (KBr tablet) |
| 550 (M+) |
| -- |
| (24a) oil (m, 4H), 3.79(s, 3H), 4.97 |
| 1715, 1607, |
| (s, 1H), 4.82&6.37(ABq, J=19.2 |
| 1310, 1248, |
| Hz, 2H), 6.7- 6.85(m, 2H), 7.1-7.5 |
| 1152, 1000 |
| (m, 10H), 7.71(dd, J=3.0, 12.9Hz, |
| 1H), 7.90(d, J=3.0Hz, 1H) |
| 53 yellow |
| 80-81 (CDCl3) 2.28-3.26(m, 12H), 3.81 |
| (KBr tablet) |
| 544 (M+) |
| C26 H28 |
| NO5 S3 |
| (25a) solid [iso- (s, 3H), 5.00(s, 1H), 4.86&6.36 |
| 1714, 1609, C H N |
| propyl |
| (ABq, J=13.2Hz, 2H), 6.68-7.98(m, |
| 1353, 1242, 57.31 |
| 5.30 |
| 5.09 |
| ether]* |
| 10H) 1007 57.33 |
| 5.18 |
| 5.14 |
| 54 colorless |
| -- (CDCl3) 2.15-2.75(m, 10H), 3.15-3.45 |
| (CHCl3) |
| 592 (M+) |
| -- |
| (27a) oil (m, 2H), 3.8-3.9(m, 12H), |
| 1713, 1613, |
| 5.04(s, 1H), 4.87&6.38(ABq, J= |
| 1461, 1295, |
| 17.1Hz, 2H), 6.62(d, J=12.9Hz, |
| 1120, 1009 |
| 1H), 6.80(d, J=12.9H, 1H), 6.91 |
| (d, J=12.9Hz, 1H), 7.1-7.47(m, |
| 4H), 7.74(dd, J=3.0, 12.9Hz, 1H), |
| 7.93(d, J=3.0Hz, 1H) |
| 55 yellow |
| -- (CDCl3) 2.19-2.70(m, 8H), 3.36-3.83 |
| (KBr tablet) |
| 528 (M+) |
| -- |
| (28a) amorphous (m, 4H), 3.83(s, 3H), 5.03(s, |
| 1711, 1645, |
| 1H), 4.85&6.41(ABq, J=12.8Hz, |
| 1606, 1245, |
| 2H), 6.61-8.06(m, 14H) |
| 982 |
| 56 white 133-135 |
| (CDCl3) 2.2-2.8(m, 8H), 3.3-3.7 |
| (KBr tablet) |
| 518 (M+) |
| C29 H30 |
| N2 O5 S |
| (30a) solid [iso- (m, 4H), 3.85(s, 3H), 4.87&6.43 |
| 1712, 1611, C H N |
| propyl |
| (ABq, J=12.8Hz, 2H), 5.04(s, 1H), |
| 1497, 1293, 67.00 |
| 5.90 |
| 5.12 |
| ether] |
| 6.83(d, J=8.4Hz, 1H), 6.95-7.5(m, |
| 1248, 1199, 67.16 |
| 5.83 |
| 5.40 |
| 9H), 7.76(dd, J=2.4, 8.4Hz, 1H), |
| 1118 |
| 7.97(d, J=2.4Hz, 1H) |
| 57 colorless |
| -- (CDCl3) 2.05-2.8(m, 8H), 3.4-3.65 |
| (neat) 532 (M+) |
| -- |
| (31a) oil (m, 4H), 3.80(s, 3H), 4.84& |
| 2948, 1710, |
| 6.39(ABq, J=12.6Hz, 2H), 5.02(s, |
| 1610, 1433, |
| 1H), 5.08(s, 2H), 6.81(d, J=8.5 |
| 1237, 1118, |
| Hz, 1H), 7.0-7.5(m, 9H), 7.74 |
| 1006 |
| (dd, J=2.4, 8.5Hz, 1H), 7.93(d, |
| J=2.4Hz, 1H) |
| 58 pale 193-196 |
| (CDCl3) 2.45-2.9(m, 4H), 3.0-3.6 |
| (KBr tablet) |
| 530 (M+) |
| C30 H30 |
| N2 O5 S |
| (E-78a) |
| yellow |
| [isopro- |
| (m, 6H), 3.91(s, 3H), 4.7-5.7(m, |
| 1715, 1607, C H N |
| crystal |
| panol] |
| 2H), 6.23(t, J=7.6Hz, 1H), 6.5-8.1 |
| 1310, 1248, 67.55 |
| 5.90 |
| 5.39 |
| (m, 14H) 1152, 1000, 67.90 |
| 5.70 |
| 5.28 |
| 945 |
| 59 colorless |
| -- (CDCl3) 2.45-2.6(m, 4H), 3.0-3.3 |
| (KBr tablet) |
| 510 (M+) |
| -- |
| (E-79a) |
| oil (m, 6H), 3.86(s, 3H), 4.7-5.7 |
| 1711, 1605, |
| (m, 2H), 6.13(t, J=6.8Hz, 1H), |
| 1351, 1241, |
| 7.0-7.65(m, 7H), 7.78(dd, J=2.2, |
| 999 |
| 8.6Hz, 1H), 6.77(d, J=8.6Hz, 1H), |
| 7.98(d, J=2.2Hz, 1H) |
| 60 colorless |
| -- (CDCl3) 1.6-2.0(m, 2H), 2.45-2.85 |
| (KBr tablet) |
| 602 (M+) |
| -- |
| (34a) oil (m, 8H), 3.3-3.6(m, 4H), 3.86 |
| 1713, 1609, |
| (s, 3H), 4.88&6.43(ABq, J=12.1 |
| 1321, 1243, |
| Hz, 2H), 4.99(s, 1H), 7.25-8.85 |
| 1005 |
| (m, 13H) |
| __________________________________________________________________________ |
In Examples 61 through 63 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]o xepin-2-carboxylic acid∅5 hydrate (Compound 24b')
11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethyl]thio -6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid∅5 isopropanol.dihydrate (Compound 25b')
11-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]-thio-6,11-dihydrodi benz[b,e]oxepin-2-carboxylic acid (Compound 27b)
11-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]-thio-6,11-dihydrodi benz[b,e]oxepin-2-carboxylic acid. monohydrochloride.1.1 hydrate (Compound 27b')
The objective compound was prepared as the hydrochloride from Compound 27b obtained in Example 63 in a manner similar to Example 2.
In Examples 65 through 68 below, the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
11-[2-[4-(Cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydro -dibenz[b,e]oxepin-2-carboxylic acid (Compound 28b)
11-2-[4-(Benzyloxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e ]oxepin-2-carboxylic acid.dehydrate (Compound 31b')
(E)-11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylic acid-0.1 iso -propanol∅1 hydrate (Compound E-78b')
PAC (E)-11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibe nz[b,e]oxepin-2-carboxylic acid∅5 hydrate (Compound E-79b')Physicochemical properties of the compounds obtained in Examples 61 to 68 are shown in Table 7-5.
| TABLE 7-5 |
| __________________________________________________________________________ |
| MP (°C.) |
| Example [Solvent |
| No. for re- Elemental analysis |
| (%) |
| (Compound |
| Appear- |
| crystal- |
| NMR IR MS Upper column: found |
| No.) ance lization] |
| (solvent) δ, ppm |
| (method) cm-1 |
| m/z Lower column: |
| __________________________________________________________________________ |
| calcd. |
| 61 white 232-235 |
| (DMSO-d6) 2.3-2.7(m, 8H), 3.0-3.3 |
| (KBr tablet) |
| -- C29 H30 |
| N2 O5 |
| S2∅5H2 O |
| (24b') |
| crystal |
| [isopro- |
| (m, 4H), 5.44(s, 1H), 5.10& |
| 1685, 1603, C H N |
| panol] 6.31(ABq, J=19.2Hz, 2H), 6.86(d, |
| 1313, 1246, 62.30 |
| 5.63 |
| 4.82 |
| J=13.5Hz, 1H), 7.25-7.65(m, 10H), |
| 1157, 1002, 62.23 |
| 5.58 |
| 5.00 |
| 7.65-7.9(m, 2H), 7.98(d, J=3.0Hz, |
| 957 |
| 1H) |
| 62 white 167-168 |
| (DMSO-d6) 2.50-3.46(m, 12H), |
| (KBr tablet) |
| 530 (M+) |
| C25 H26 |
| N2 O5 |
| S3∅5 |
| (25b') |
| crystal |
| [isopro- |
| 5.05&6.17(ABq, J= 12.7Hz, 2H), |
| 3400, 2860, C3 H8 |
| O.2H2 O |
| panol] 5.47(s, 1H), 6.86-8.11(m, 10H), |
| 1687, 1607, C H N |
| 12.76(bs, 1H) 1354, 1159 53.53 |
| 5.20 |
| 4.55 |
| 53.34 |
| 5.41 |
| 4.69 |
| 63 pale -- (DMSO-d6) 2.85-3.65(m, 12H), |
| -- 578 (M+) |
| -- |
| (27b) yellow 3.75-3.85(m, 9H), 5.52(s, 1H), |
| amorphous 5.09&6.15(ABq, J=12.9Hz, 2H), |
| 6.85-7.00(m, 3H), 7.4-7.5(m, 4H), |
| 7.73(dd, J=2.1, 8.6Hz, 1H), |
| 8.04(d, J=2.1Hz, 1H) |
| 64 white 165-168 |
| -- (KBr tablet) |
| -- C31 H34 |
| N2 O7 |
| S.HCl.1H2 O |
| (27b') |
| crystal |
| [iso- 2934, 1583, C H N |
| propyl 1462, 1227, 58.63 |
| 6.23 |
| 4.23 |
| ether] 1011 58.64 |
| 5.90 |
| 4.41 |
| 65 white 218-219 |
| (DMSO-d6) 2.25-3.75(m, 12H), |
| (KBr tablet) |
| 514 (M+) |
| C30 H30 |
| N2 O4 S |
| (28b) crystal |
| [isopro- |
| 5.05&6.28(ABq, J=12.5Hz, 2H), |
| 1692, 1642, C H N |
| panol] 5.45(s, 1H), 6.87(d, J=8.5Hz, |
| 1566, 1227, 69.91 |
| 5.96 |
| 5.39 |
| 1H), 7.24(d, J=15.5Hz, 1H), 7.3-7.5 |
| 1004, 987 70.02 |
| 5.88 |
| 5.44 |
| (m, 5H), 7.48(d, J=15.5Hz, |
| 1H), 7.65-7.8(m, 3H), 8.00(d, J= |
| 2.1Hz, 1H) |
| 66 white 207-208 |
| (DMSO-d6) 2.8-4.2(m, 12H), 5.12 |
| (KBr tablet) |
| 518 (M+) |
| C29 H30 |
| N2 O5 |
| S.2H2 O |
| (31b') |
| crystal |
| [toluene] |
| (s, 2H), 5.09&6.15(ABq, J=12.9 |
| 1714, 1677, C H N |
| Hz, 2H), 5.52(s, 1H), 6.90(d, J= |
| 1611, 1436, 62.43 |
| 6.51 |
| 4.96 |
| 8.6Hz, 1H), 7.3-7.6(m, 9H), 7.73 |
| 1200, 1161, 62.80 |
| 6.18 |
| 5.05 |
| (dd, J=2.2, 8.6Hz, 1H), 8.04(d, |
| 1005 |
| J=2.2Hz, 1H), 11.25(bs, 1H) |
| 67 white 233-235 |
| (DMSO-d6) 2.2-3.5(m, 10H), 5.00 |
| (KBr tablet) |
| 516 (M+) |
| C29 H28 |
| N2 O 5 S. |
| (E-78b') |
| crystal |
| (dec.) &5.52(each bs, 2H), 6.10(t, J= |
| 1685, 1603, 0.5H2 O∅1C3 |
| H8 O |
| [isopro- |
| 6.6Hz, 1H), 6.83(d, J=8.5Hz, 1H), |
| 1570, 1348, C H N |
| panol] 7.2-7.9(m, 11H) 1313, 1246, 66.37 |
| 5.70 |
| 5.11 |
| 1002, 957 66.20 |
| 5.65 |
| 5.27 |
| 68 white 250-251 |
| (DMSO-d6) 2.3-3.5(m, 10H), 4.99 |
| (KBr tablet) |
| 496 (M+) |
| C25 H24 |
| N2 O5 |
| S2∅5H2 O |
| (E-79b') |
| crystal |
| (dec.) &5.50(each bs, 2H), 6.07(bs, |
| 1685, 1607, C H N |
| [isopro- |
| 1H), 6.82(d, J=8.5Hz, 1H), 7.2-7.65 |
| 1353, 1316, 59.33 |
| 4.74 |
| 5.47 |
| panol] (m, 6H), 7.71(dd, J=2.2, 8.5 |
| 1246, 1166, 59.39 |
| 4.98 |
| 5.54 |
| Hz, 1H), 7.87(d, J=2.2Hz, 1H), |
| 1009, 954 |
| 8.05-8.10(m, 1H) |
| __________________________________________________________________________ |
| ______________________________________ |
| Pharmaceutical Preparation 1 Tablet |
| A tablet having the following composition is |
| prepared in a conventional manner. |
| ______________________________________ |
| Compound 1b' 100 mg |
| Lactose 60 mg |
| Potato starch 30 mg |
| Polyvinyl alcohol 2 mg |
| Magnesium stearate 1 mg |
| Tar pigment trace |
| ______________________________________ |
| Pharmaceutical Preparation 2 Powder |
| Powders having the following composition are |
| prepared in a conventional manner. |
| ______________________________________ |
| Compound 38b' 100 mg |
| Lactose 300 mg |
| ______________________________________ |
| Pharmaceutical Preparation 3 Syrup |
| Syrup having the following composition is pre- |
| pared in a conventional manner. |
| ______________________________________ |
| Compound 38b' 100 mg |
| Refined sugar 30 g |
| Ethyl p-hydroxybenzoate 40 mg |
| Propyl p-hydroxybenzoate |
| 10 mg |
| Strawberry flavor 0.1 cc |
| Water is added until the whole volume is 100 cc. |
| ______________________________________ |
| Pharmaceutical Preparation 4 Tablet |
| A tablet having the following composition is |
| prepared in a conventional manner. |
| ______________________________________ |
| Compound E-78b' 100 mg |
| Lactose 60 mg |
| Potato starch 30 mg |
| Polyvinyl alcohol 2 mg |
| Magnesium stearate 1 mg |
| Tar pigment trace |
| ______________________________________ |
| Pharmaceutical Preparation 5 Syrup |
| Syrup having the following composition is prepared |
| in a conventional manner. |
| ______________________________________ |
| Compound E-78b' 100 mg |
| Refined sugar 30 g |
| Ethyl p-hydroxybenzoate 40 mg |
| Propyl p-hydroxybenzoate |
| 10 mg |
| Strawberry flavor 0.1 cc |
| Water is added until the whole volume is 100 cc. |
| ______________________________________ |
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Karasawa, Akira, Kubo, Kazuhiro, Oshima, Etsuo, Obase, Hiroyuki, Miki, Ichiro, Ishii, Akio, Ohmori, Kenji, Ishii, Hidee
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